rs281864900

chr11-5226762-CAAAG-Cchr11-5226762-C-CAAAG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000518.5(HBB):c.126_129del(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 (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

HBB
NM_000518.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:1

Conservation

PhyloP100: 8.66

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 245 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5226762-CAAAG-C is Pathogenic according to our data. Variant chr11-5226762-CAAAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226762-CAAAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.126_129del	p.Phe42LeufsTer19	frameshift_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.126_129del	p.Phe42LeufsTer19	frameshift_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000278

AC:

AN:

251398

Hom.:

AF XY:

0.000339

AC XY:

AN XY:

135860

show subpopulations

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 SAS exome

AF:

0.000882

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.:

AF XY:

0.000117

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00108

Gnomad4 SAS exome

AF:

0.000962

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00212

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000113

Hom.:

Bravo

AF:

0.0000831

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2021	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 06, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Aug 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	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. -

beta Thalassemia

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000518.4(HBB):c.126_129delCTTT(F42Lfs19) 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(F42Lfs19) 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. -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 12, 2016	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 31, 2018	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

Beta-thalassemia HBB/LCRB

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 04, 2021	- -

Beta zero thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 28, 2002

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2015

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. -

alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:Methemoglobinemia, beta-globin type;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 08, 2022

- -

HBB-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Hb SS disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over