GeneBe

11-5226779-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000518.5(HBB):​c.113G>A​(p.Trp38*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

HBB
NM_000518.5 stop_gained

Scores

4
2
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 4.55

Publications

14 publications found
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 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

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5226779-C-T is Pathogenic according to our data. Variant chr11-5226779-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 439782.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
HBBNM_000518.5 linkc.113G>A p.Trp38* stop_gained Exon 2 of 3 ENST00000335295.4 NP_000509.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBBENST00000335295.4 linkc.113G>A p.Trp38* stop_gained Exon 2 of 3 1 NM_000518.5 ENSP00000333994.3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

beta Thalassemia Pathogenic:2
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

- -

Mar 17, 2017
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

not specified Pathogenic:1
Jan 24, 2017
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Pathogenic:1
Feb 14, 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.Trp38*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Beta thalassemia (PMID: 28670940). ClinVar contains an entry for this variant (Variation ID: 439782). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.31
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.62
CADD
Pathogenic
42
DANN
Uncertain
1.0
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Uncertain
0.92
D
PhyloP100
4.5
Vest4
0.83
GERP RS
5.1
PromoterAI
-0.014
Neutral
Mutation Taster
=1/199
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs33991059; hg19: chr11-5248009; COSMIC: COSV105243421; COSMIC: COSV105243421; API