11-5227003-CAG-C

Variant names:

• chr11-5227003-CAG-C
• rs34889882
• NM_000518.5:c.17_18delCT

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS2_Supporting

The NM_000518.5(HBB):​c.17_18delCT​(p.Pro6ArgfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,611,036 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P6P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: HBB NM_000518.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 1.43
• Publications: 34 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 15 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 316 pathogenic variants in the truncated region.
• PP5: Variant 11-5227003-CAG-C is Pathogenic according to our data. Variant chr11-5227003-CAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 15422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD,SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.17_18delCT	p.Pro6ArgfsTer17	frameshift_variant	Exon 1 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.17_18delCT	p.Pro6ArgfsTer17	frameshift_variant	Exon 1 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152216 Hom.: 2 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: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251156 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1458702 Hom.: 0 AF XY: 0.0000303 AC XY: 22 AN XY: 725878

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1109156

Other (OTH) AF: 0.00 AC: 0 AN: 60284

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152334 Hom.: 2 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74508

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.17_18delCT; p.Pro6ArgfsTer17 variant (rs34889882, HbVarID: 783), also known as Codon 5 (-CT) or Pro5fs when numbered from the mature protein, has been reported in the literature in an individual with beta(0) thalassemia (Kollia 1989, HbVar database and references therein). This variant is reported as pathogenic in ClinVar (Variation ID: 15422). It is found in the general population with an overall allele frequency of 0.004% (11/251156 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 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 database: https://globin.bx.psu.edu/hbvar/menu.html Kollia et al. Frameshift codon 5 (Fsc-5 (-CT)) thalassemia; a novel mutation detected in a Greek patient. Hemoglobin. 1989;13(6):597-604. PMID: 2606727. -

Jan 05, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 22, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.17_18del (p.Pro6Argfs*17) variant (also known as CD5 (-CT)) alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. In the published literature, this variant has been reported in the compound heterozygous and homozygous state in individuals with beta-thalassemia major and intermedia (PMIDs: 33491330 (2021), 27263053 (2016), 25617386 (2015), 2606727 (1989)). Based on the available information, this variant is classified as pathogenic. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2023

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.Pro6Argfs*17) 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 (rs34889882, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with beta thalassemia (PMID: 2606727). This variant is also known as Pro5fs and FSC-5(-CT). ClinVar contains an entry for this variant (Variation ID: 15422). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Aug 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

beta Thalassemia Pathogenic:5

Jun 06, 2017

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 HBB c.17_18delCT is a frame-shift variant resulting in termination of translation at codon 23, which is predicted to cause either a truncated or absent HBB protein through non-sense mediated decay which is a commonly known mechanism for BTHAL. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Leu29fs). This variant is found in 1/121340 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the maximal expected frequency of a pathogenic allele (0.0111803) in this gene. This variant has been commonly identified in beta-thalassemia patients in both compound heterozygous and homozygous states. It is also reported as one of the common mutations in Middle Eastern countries (Lahiry_2008). Taken together, this variant has been classified as a disease variant/pathogenic. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro6ArgfsX17 variant in HBB has been reported in several individuals with beta thalassemia and is one of the common pathogenic variants in Middle Eastern countries ( selected references Kollia 1989 PMID: 2606727, Vetter 1997 PMID: 9163586, Murad 2021 PMID: 33491330). It has also been reported in ClinVar (Variation ID 15422) and was identified in 6/4834 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 6 and leads to a premature termination codon 17 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta thalassemia. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3_Strong. -

Beta-thalassemia HBB/LCRB Pathogenic:4

May 08, 2018

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 07, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000015422 /PMID: 2606727). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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.17_18delCT (NP_000509.1:p.Pro6fs ) is a frame-shift variant, which is also a beta 0 mutation. When this variant present with other pathogenic HBB mutation leads to severe type of thalassemia. Patients needing blood transfusion, often presented with hepatosplenomegaly, Iron overload. The frequency of the variant among thalassemia patient in Eastern India is 0.19 % 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] -

Dominant beta-thalassemia Pathogenic:1

Dec 27, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4,PM2_SUP -

Beta zero thalassemia Pathogenic:1

Jan 01, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HBB-related disorder Pathogenic:1

Feb 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HBB c.17_18delCT variant is predicted to result in a frameshift and premature protein termination (p.Pro6Argfs*17). This variant is also known as Codon 5 [-CT], FSC-5(-CT), or CD 5 -CT in the literature. This variant was reported in the homozygous and compound heterozygous states to be causative for autosomal recessive beta-thalassemia (Kollia et al. 1989. PubMed ID: 2606727; Elmezayen et al. 2015. PubMed ID: 25617386; Murad et al. 2021. PubMed ID: 33491330). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in HBB are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Apr 27, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=5/195	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: rs34889882; hg19: chr11-5248233;