rs33922842

Positions:

• chr11-5226762-C-A
• chr11-5226762-C-G
• chr11-5226762-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000335295.4(HBB):​c.130G>T​(p.Glu44Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB ENST00000335295.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: -0.219

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]

ACMG classification

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 241 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5226762-C-A is Pathogenic according to our data. Variant chr11-5226762-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 15406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226762-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.130G>T	p.Glu44Ter	stop_gained	2/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.130G>T	p.Glu44Ter	stop_gained	2/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251398 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 08, 2018	The HBB c.130G>T; Glu43Ter variant (rs33922842), also known as Codon 43 (G>T), is reported in the medical literature in an individual with beta thalassemia who also carried an additional nonsense variant on the opposite chromosome (Atweh 1988, see link to HbVar below). The variant is described as pathogenic in the ClinVar database (Variation ID: 15406). The variant is also listed in the Genome Aggregation Database in 1 out of 246166 alleles. This variant introduces a premature termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. In agreement with that prediction, this variant is shown to have reduced mRNA levels when transfected and absent mRNA levels in cells derived from the individual who carried this variant and an additional nonsense variant on the opposite chromosome (Athweh 1988). Considering available information, this variant is classified as pathogenic. References: Link to Glu43Ter in HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=853&.cgifields=histD Atweh GF et al. New amber mutation in a beta-thalassemic gene with nonmeasurable levels of mutant messenger RNA in vivo. J Clin Invest. 1988 Aug;82(2):557-61. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 19, 2021	The c.130G>T (p.Glu44*) pathogenic variant (also known as Codon 43 (G>T)) causes the premature termination of beta globin protein synthesis, and is associated with beta(0)-thalassemia PMIDs: 3403716 (1988), 17008283 (2006), 25000193 (2014)). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2022	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30275481, 31690135, 3403716, 17008283) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2023	This sequence change creates a premature translational stop signal (p.Glu44*) 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 (rs33922842, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with beta-thalassemia (PMID: 3403716, 25089872). This variant is also known as p.Glu43*. ClinVar contains an entry for this variant (Variation ID: 15406). For these reasons, this variant has been classified as Pathogenic. -

beta Thalassemia Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 19, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 24, 2017	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

Beta zero thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1988

- -

Hemoglobinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 14, 2017

Variant summary: The HBB c.130G>T (p.Glu44X) 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.176delC, c.217dupA, c.287dupA, etc.). This variant was found in 1/246166 control chromosomes at a frequency of 0.0000041 (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant has been found three Chinese BTHAL patients in compound heterozygous state with other pathogenic variants (Atwen_1988, Tan_2006). Two of them were BTHAL major patients who carried this variant in compound heterozygous state with c.127_130delCTTT. In addition, several BTHAL minor individuals who carry this variant in heterozygous state have been reported (Lin_2014, He_2017). The carrier frequency in a large Chinese population was 0.03% (He_2017). A functional analysis showed that the mutant mRNA in vivo must be extremely low (Atwen_1988). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Beta-thalassemia HBB/LCRB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PVS1+PS4+PP4 -

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	0.49	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.24	N
MutationTaster	Benign	1.0	A
Vest4		0.71
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs33922842; hg19: chr11-5247992;