Genetic Variant HBB:p.Trp38* (chr11-5226778-C-T) – ACMG Classification: Pathogenic (18 pts)

Variant summary

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

The NM_000518.5(HBB):c.114G>A(p.Trp38*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,254 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

HBB
NM_000518.5 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.34

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 114 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-5226778-C-T is Pathogenic according to our data. Variant chr11-5226778-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226778-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.114G>A	p.Trp38*	stop_gained	Exon 2 of 3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.114G>A	p.Trp38*	stop_gained	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jun 23, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.114G>A (p.Trp38*) variant (also known as Codon 37 (G>A) and W37X) causes the premature termination of beta-globin (HBB) protein synthesis and is associated with beta(0)-thalassemia (PMID: 3006832 (1986), 15008262 (2004), 18096416 (2008), 23321370 (2013), 23510507 (2013)). -

Jan 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.114G>A; p.Trp38Ter variant (rs33974936, HbVar ID: 841), also known as Codon 37 (G->A), is reported in multiple individuals diagnosed with beta-thalassemia, and associated with beta-0 trait (Asadov 2013, Boehm 1986, Fernandes 2011, Gallano 1992, HbVar database and references therein). This variant is also reported in ClinVar (Variation ID: 15405) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and 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 Asadov C et al. Identification of two rare Beta-globin gene mutations in a patient with Beta-thalassemia intermedia from Azerbaijan. Hemoglobin. 2013; 37(3):291-6. PMID: 23510507. Boehm C et al. Use of oligonucleotide hybridization in the characterization of a beta zero-thalassemia gene (beta 37 TGG----TGA) in a Saudi Arabian family. Blood. 1986; 67(4):1185-8. PMID: 3006832. Fernandes A et al. Molecular analysis of B-thalassemia patients: first identification of mutations HBB:c.93-2A>G and HBB:c.114G>A in Brazil. Hemoglobin. 2011; 35(4):358-66. PMID: 21797703. Gallano P et al. High prevalence of the beta-thalassaemia nonsense 37 mutation in Catalonians from the Ebro delta. Br J Haematol. 1992; 81(1):126-7. PMID: 1520612. -

Mar 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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: 3006832, 28670940). ClinVar contains an entry for this variant (Variation ID: 15405). -

Jun 09, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Reported as pathogenic in a well-curated hemoglobin database but additional evidence is not available (Giardine et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 22385009, 3006832, 23510507, 21797703) -

beta Thalassemia

Pathogenic:3

Dec 16, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

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

- -

Beta zero thalassemia

Pathogenic:1

Apr 01, 1986

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hemoglobinopathy

Pathogenic:1

Dec 18, 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.114G>A (p.Trp38X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.118C>T/p.Gln40X, c.130G>T/p.Glu44X, etc). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 30964 control chromosomes. It has been reported in many BTHAL patients (both intermediate and major types) in both homozygous and comound heterozygous status. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/ likely pathogenic. Ithanet lists variant as ' Globin gene causative mutation' with relative frequencies of 6.3% in Jordan, 4.05% in Syria, 1.08% in Tunisia, 1% in Egypt, 0.3% in Czech Republic, 0.3% in Slovakia, 0.3% in Pakistan, and 0.3% in Spain. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.96

Vest4

0.83

GERP RS

5.1

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