chr11-5226975-C-T

Position:

chr11-5226975-C-T

Variant summary

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

The NM_000518.5(HBB):c.47G>A(p.Trp16Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

HBB
NM_000518.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 1.62

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 located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 343 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5226975-C-T is Pathogenic according to our data. Variant chr11-5226975-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 15403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226975-C-T 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.47G>A	p.Trp16Ter	stop_gained	1/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.47G>A	p.Trp16Ter	stop_gained	1/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152208

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:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000876

AC:

AN:

251244

Hom.:

AF XY:

0.0000958

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461398

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000522

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74500

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:

0.000828

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000171

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

beta Thalassemia

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 12, 2016	Variant summary: The HBB c.47G>A (p.Trp16X) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Variant c.48G>A that gives the same codon change has been classified as pathogenic by our laboratory. One in silico tool predicts a damaging outcome for this variant. This variant was found in 14/121364 control chromosomes at a frequency of 0.0001154, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been reported in numerous beta thalassemia patients and is considered as a common disease variant. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 03, 2022	The p.Trp16X variant (also known as Trp15X) has been reported in numerous individuals with beta thalassemia (selected references Kazazian 1984 PMID: 6714226, HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=791 ). It has been reported in ClinVar (Variation ID 15403) and was identified in 4/4834 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 16, which is 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	Myriad Genetics, Inc.	Dec 16, 2019	NM_000518.4(HBB):c.47G>A(W16) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with beta thalassemia. Sources cited for classification include the following: PMID 21389146, 15278762, 18294253 and 21389146. Classification of NM_000518.4(HBB):c.47G>A(W16) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. 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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	The HBB c.47G>A; p.Trp16Ter variant (also known as Trp15Ter when numbered from the mature protein or as Codon 15 (G->A); TGG->TAG, rs63750783, HbVar ID: 791) has been reported in individuals with beta(0) thalassemia (Kazazian 1984, HbVar database and references therein). This variant is found in the general population with an overall allele frequency of 0.009% (22/251244 alleles) in the Genome Aggregation Database. This variant introduces a premature termination codon, but the mRNA is resistant to nonsense-mediated decay (Neu-Yilik 2011); thus it is predicted to result in a truncated protein. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Kazazian HH Jr et al. Molecular characterization of seven beta-thalassemia mutations in Asian Indians. EMBO J. 1984; 3(3):593-6. PMID: 6714226. Neu-Yilik G et al. Mechanism of escape from nonsense-mediated mRNA decay of human beta-globin transcripts with nonsense mutations in the first exon. RNA. 2011; 17(5):843-54. PMID: 21389146. -
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	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change creates a premature translational stop signal (p.Trp16*) in the HBB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 132 amino acid(s) of the HBB protein. This variant is present in population databases (rs63750783, gnomAD 0.06%). This premature translational stop signal has been observed in individuals with beta thalassemia and has been reported as a prevalent disease-associated variant in several populations (PMID: 1581247, 6714226, 7668221, 18294253, 20395516, 27263053, 27828729). This variant is also known as "Codon 15 (TGG->TGA)". ClinVar contains an entry for this variant (Variation ID: 15403). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 11, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2023	Nonsense 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: 22975760, 30200837, 29669226, 7668221, 6714226, 28635337, 21389146, 8091935, 27263053) -

Beta-thalassemia HBB/LCRB

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gain c.47G>A (p.Trp16Ter) variant in the HBB gene has been reported previously in both homozygous and compound heterozygous states in multiple individuals affected with beta-thalassemia and is also one of the most common HBB variants causing beta-thalassemia (Yasmeen et al. 2016; Panja et al. 2017). The p.Trp16Ter variant is reported with an allele frequency of 0.008% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant is predicted to cause a loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease-causing. For these reasons, this variant has been classified as Pathogenic. As this variant in HBB gene is in heterozygous state, it is suggestive of Beta thalassemia trait. -
Pathogenic, no assertion criteria provided	clinical testing	MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN	May 07, 2024	The HBB c.47G>A; p.Trp16Ter variant, it is a beta 0 type of mutation, The variant introduce a premature termination codon results into nonsense mediated decay of HBB mRNA. The frequency of this variant among thalassemia patient in Eastern India is 2.10 % 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

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1992

- -

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

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.89

MutationTaster

Benign

1.0

Vest4

0.66

GERP RS

4.3

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