Variant rs34889882 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The ENST00000335295.4(HBB):c.17_18del(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
ENST00000335295.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 1.43

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 16 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 380 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 id is 15422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227003-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.17_18del	p.Pro6ArgfsTer17	frameshift_variant	1/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.17_18del	p.Pro6ArgfsTer17	frameshift_variant	1/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152216

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:

0.00

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

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251156

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1458702

Hom.:

AF XY:

0.0000303

AC XY:

AN XY:

725878

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000631

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:6

Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 06, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 08, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Jan 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 22, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	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. -

Beta-thalassemia HBB/LCRB

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN	May 07, 2024	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] -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

Beta zero thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1989

- -

alpha Thalassemia;C0002895: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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 12, 2021

- -

HBB-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2024

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

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

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