NM_000518.5:c.126_129delCTTT

Variant names:

• chr11-5226762-CAAAG-C
• rs80356821
• NM_000518.5:c.126_129delCTTT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000518.5(HBB):​c.126_129delCTTT​(p.Phe42LeufsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000923 in 1,614,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: HBB NM_000518.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25 O:1
• Conservation: PhyloP100: 8.66
• Publications: 35 publications found

Genes affected

HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

HBB Gene-Disease associations (from GenCC):

• dominant beta-thalassemia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• hemoglobin M disease

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
• beta thalassemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• beta-thalassemia HBB/LCRB

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• erythrocytosis, familial, 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Heinz body anemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• sickle cell disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia intermedia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia major

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• delta-beta-thalassemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-beta-thalassemia disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin c disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin d disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin E disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-5226762-CAAAG-C is Pathogenic according to our data. Variant chr11-5226762-CAAAG-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 15417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.126_129delCTTT	p.Phe42LeufsTer19	frameshift_variant	Exon 2 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.126_129delCTTT	p.Phe42LeufsTer19	frameshift_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000278 AC: 70 AN: 251398 AF XY: 0.000339

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00234

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000917 AC: 134 AN: 1461876 Hom.: 0 AF XY: 0.000117 AC XY: 85 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00108 AC: 43 AN: 39700

South Asian (SAS) AF: 0.000962 AC: 83 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.000132 AC: 8 AN: 60396

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000113 Hom.: 0

Bravo AF: 0.0000831

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:25 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Jan 06, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 29, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 22, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.126_129del; p.Phe42LeufsTer19 variant (also known as Phe41fs when numbered from the mature protein or as codon 41/42-TTCT, rs80356821, HbVar ID: 849) has been reported in the homozygous and compound heterozygous states in individuals affected with beta(0) thalassemia (see link to HbVar, Kimura 1983). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 15417) and is observed in the general population at an overall frequency of 0.02% (73/282786 alleles) with increased frequency in the East Asian population (0.2%) in the Genome Aggregation Database. This variant creates a frameshift by deleting 4 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/hbvar.html Kimura A et al. Structural analysis of a beta-thalassemia gene found in Taiwan. J Biol Chem. 1983 Mar 10;258(5):2748-9. PMID: 6826539. -

Nov 04, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Phe42Leufs*19) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs281864900, gnomAD 0.2%). This premature translational stop signal has been observed in individuals with HBB-related conditions (PMID: 6826539, 25089872, 28635337). ClinVar contains an entry for this variant (Variation ID: 15417). For these reasons, this variant has been classified as Pathogenic. -

Nov 03, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20181291, 22975760, 6826539, 11224481, 24200214, 28635337, 26096776, 30487145, 30945812, 31111750, 31930713, 30275481, 10870880, 33198537, 8091935) -

beta Thalassemia Pathogenic:5 Other:1

Apr 12, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.126_129delCTTT variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.135delC, c.143_146dupATCT). Mutation taster predicts damaging outcome for this variant. This variant is found in 33/121370 control chromosomes at a frequency of 0.0002719, which does not exceed maximal expected frequency of a pathogenic allele (0.0111803). This variant is reported in the literatures as a well-known pathogenic variant predominantly identified in East and South Asian. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -

Nov 25, 2019

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Oct 31, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.126_129delCTTT (p.Phe42LeufsTer19) variant, also described as codon 41/42 (-CTTT) or codon 41/42 (-TTCT), results in a frameshift and is predicted to result in premature truncation of the protein. This variant is particularly prevalent in the Chinese population and is usually associated with a beta-thalassemia phenotype (Lin et al. 2014; Zhang et al. 2015; Yu et al. 2015; Origa et al 2015). Across a selection of the available literature, the p.Phe42LeufsTer19 variant has been identified in a homozygous state in one individual and in a compound heterozygous state in seven individuals, all with beta-thalassemia (Kimura et al. 1983; Hernanda et al. 2012; Huang et al. 2014; Italia et al. 2015; Rujito et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00496 in the East Asian population of the 1000 Genomes. Based on the evidence and the potential impact of frameshift variants, the p.Phe42LeufsTer19 variant is interpreted as pathogenic for beta-thalassemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000518.4(HBB):c.126_129delCTTT(F42Lfs*19) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy; it is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 6826539, 25000193, 6714226 and 25480500. Classification of NM_000518.4(HBB):c.126_129delCTTT(F42Lfs*19) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

Beta-thalassemia HBB/LCRB Pathogenic:5

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM3_VeryStrong+PP4 -

Nov 04, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant c.126_129del (p.Phe42LeufsTer19) in HBB gene has been observed in the homozygous and compound heterozygous state in several individuals with HBB-related conditions (Kimura A et al., 1983). This sequence change creates a premature translational stop signal (p.Phe42Leufs*19) in the HBB gene. It is expected to result in an absent or disrupted protein product. This variant is present in the gnomAD database with a frequency of 0.03%. Loss-of-function variants in HBB are known to be pathogenic (Craig JE et al., 1994). This variant has been reported to the ClinVar database as Pathogenic. For these reasons, this variant has been classified as Pathogenic. -

-

Lifecell International Pvt. Ltd

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A Heterozygous Frameshift variant c.126_129delCTTT in Exon 2 of the HBB gene that results in the premature termination of the protein (p.Phe42fs*19) was identified. The observed variant has a minor allele frequency of 0.00028% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect ofthe protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination ofscores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons.The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant was found inClinVar (Variant ID :15417) with a classification of Pathogenic/Likely Pathogenic and a review status of (2 star) criteria provided, multiple submitters, no conflicts. The variant is reported in many patients with beta thalassemia (Chen W et al.,2010). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

May 07, 2024

MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HBB c.126_129delCTTT (NP_000509.1:p.Phe42fs ) is a frameshift variant leads to a premature termination of HBB mRNA. The variant also describe as beta0 mutation, When this variant present in homozygous or in compound heterozygous with other pathogenic HBB mutation leads to severe anemia, The condition known as beta thalassemia major. The frequency of this variant among thalassemia patient in Eastern India is 2.68 % as per our multicentric project - A Genetic Diagnostic Algorithm Based Study for Thalassemia in Northern and Eastern Indian Populations", Funded by Dept. of Biotechnology , Govt of India [Project No. BT/PR26461/MED/12/821/2018] -

Beta zero thalassemia Pathogenic:1

Sep 28, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Nov 25, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.126_129delCTTT pathogenic mutation (also known as codons 41/42 (-TTCT) and c.124_127delTTCT), located in coding exon 2 of the HBB gene, results from a deletion of 4 nucleotides between positions 126 and 129, causing a translational frameshift with a predicted alternate stop codon (p.F42Lfs*19). This mutation is associated with beta0-thalassemia and was originally reported as homozygous in a Chinese patient (Kimura A et al. J Biol Chem. 1983;258(5):2748-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

HBB-related disorder Pathogenic:1

Jan 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HBB c.126_129delCTTT variant is predicted to result in a frameshift and premature protein termination (p.Phe42Leufs*19). This variant was reported in individuals with beta-thalassemia (see for example Kazazian et al. 1984. PubMed ID: 6714226; Lau et al. 1997. PubMed ID: 9113933; Lin et al. 2021. PubMed ID: 34271589). This variant is reported in 0.23% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in HBB are expected to be pathogenic. This variant is interpreted as pathogenic. -

Fetal hemoglobin quantitative trait locus 1 Pathogenic:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1

Jan 10, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1

May 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hb SS disease Pathogenic:1

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary persistence of fetal hemoglobin Pathogenic:1

Mar 16, 2022

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80356821; hg19: chr11-5247992;