rs33950507

chr11-5226943-C-Achr11-5226943-C-Gchr11-5226943-C-T

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.15

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. There are 301 pathogenic variants in the truncated region.
• PM2: Very rare variant; Number of alleles below threshold, Median coverage is 32.
• 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
HBB	NM_000518.5	c.79G>T	p.Glu27Ter	stop_gained	1/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.79G>T	p.Glu27Ter	stop_gained	1/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK:

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 17, 2021	The Codon 26 (G>T) variant (HBB: c.79G>T; p.Glu27Ter, also known as Glu26Ter when numbered from the mature protein, rs33950507) 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 general population databases (Exome Variant Server, 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 link to Codon 26 (G>T): https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=808 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 12, 2021	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). This variant is not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with beta thalassemia (PMID: 1974422). This variant is also known as codon 26 GAG>TAG. ClinVar contains an entry for this variant (Variation ID: 38650). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 30, 2017	- -

beta Thalassemia Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 17, 2017	- -
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	Counsyl	Jun 04, 2018	- -

Hemoglobinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 14, 2017

Variant 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

43

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs33950507; hg19: chr11-5248173;