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rs33950507

Variant summary

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

The NM_000518.5(HBB):c.79G>T(p.Glu27Ter) 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
NM_000518.5 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 1.15
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]

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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 309 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-5226943-C-A is Pathogenic according to our data. Variant chr11-5226943-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 38650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226943-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBBNM_000518.5 linkuse as main transcriptc.79G>T p.Glu27Ter stop_gained 1/3 ENST00000335295.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBBENST00000335295.4 linkuse as main transcriptc.79G>T p.Glu27Ter stop_gained 1/31 NM_000518.5 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

beta Thalassemia Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingCounsylJun 04, 2018- -
Pathogenic, no assertion criteria providedcurationThe ITHANET community portal, The Cyprus Institute of Neurology and GeneticsNov 25, 2019- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Aug 17, 2017- -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJun 30, 2017- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeApr 17, 2021For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with beta thalassemia (PMID: 1974422). It is known as codon 26 GAG>TAG. ClinVar contains an entry for this variant (Variation ID: 38650). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu27*) 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). -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 21, 2023The Codon 26 (G>T) variant (HBB: c.79G>T; p.Glu27Ter, also known as Glu26Ter when numbered from the mature protein, rs33950507, HbVar ID: 808) is reported in an individual with beta thalassemia that also harbored the HbE variant (HbVar database and references therein). In testing performed at ARUP Laboratories, this variant has also been observed in trans to a frameshift variant in an individual with severe anemia. The p.Glu27Ter variant 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. Consistent with predictions, functional studies demonstrate an absence of beta globin protein and mRNA in cells expressing this variant (Neu-Yilik 2011). Based on available information, this variant is considered to be pathogenic. References: HbVar database link: https://globin.bx.psu.edu/hbvar/menu.html 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 May;17(5):843-54. PMID: 21389146. -
Hemoglobinopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 14, 2017Variant summary: The HBB c.79G>T (p.Glu27X, also known as CD26 G>T) 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.85dupC/p.Leu29fsX16, c.110delC/p.Pro37fsX25, etc.). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 277088 control chromosomes. It has been reported in multiple affected individuals. Variant involving the same neucleotide c.79G>A/p.Glu27Lys is a common HbE variant and the region around codon 26 has been suggested as mutation hotspot(Fucharoen_1990). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.53
Cadd
Pathogenic
44
Dann
Uncertain
1.0
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Uncertain
0.89
D
MutationTaster
Benign
1.0
A
Vest4
0.40
GERP RS
4.3

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.19
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.

Other links and lift over

dbSNP: rs33950507; hg19: chr11-5248173; API