chr11-5226604-C-CT

Position:

• chr11-5226604-C-CT

Variant summary

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

The NM_000518.5(HBB):​c.287_288insA​(p.Leu97AlafsTer6) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.47

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 64 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5226604-C-CT is Pathogenic according to our data. Variant chr11-5226604-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 36309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.287_288insA	p.Leu97AlafsTer6	frameshift_variant	2/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.287_288insA	p.Leu97AlafsTer6	frameshift_variant	2/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 14, 2018	Variant summary: HBB c.287dupA (p.Leu97AlafsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (eg. c.323dupG/p.Asn109fsX32). The variant was absent in 277156 control chromosomes (gnomAD). c.287dupA has been reported in the literature in multiple individuals affected with Beta Thalassemia Major (Winichagoon_1992, Cai_1996, Doro_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 10, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the HBB protein. Other variant(s) that disrupt this region (p.Asn109Glnfs*32) have been determined to be pathogenic (PMID: 1728311, 1897518, 3683554, 9401495). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed to segregate with beta thalassemia in a family (PMID: 8889595). ClinVar contains an entry for this variant (Variation ID: 36309). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the HBB gene (p.Leu97Alafs*6). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 51 amino acids of the HBB protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 20, 2021	The HBB c.287dup (p.Leu97Alafs*6) pathogenic variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant is associated with beta(0)-thalassemia, and is commonly found in individuals with beta-thalassemia in Southeast Asia (PMIDs: 12353305 (2002), 8889595 (1996), 1515453 (1992)). Previous names for this pathogenic variant include Codon 95 (+A), c.287_288insA and c.287dupA. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs34937014; hg19: chr11-5247834;