rs63751076

Positions:

• chr11-5226902-AAACCTGTCTTGTAACCTTGATACCAACCTGCCCAGGGCCTCACC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000518.5(HBB):​c.76_92+27del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.304

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5226902-AAACCTGTCTTGTAACCTTGATACCAACCTGCCCAGGGCCTCACC-A is Pathogenic according to our data. Variant chr11-5226902-AAACCTGTCTTGTAACCTTGATACCAACCTGCCCAGGGCCTCACC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15445.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-5226902-AAACCTGTCTTGTAACCTTGATACCAACCTGCCCAGGGCCTCACC-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.76_92+27del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	1/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.76_92+27del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	1/3	1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Beta zero thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1984

- -

Hemoglobinopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jun 05, 2023

Variant summary: HBB c.76_92+27del44 is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material, in addition to removing part of the coding sequence of exon 1. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251226 control chromosomes (gnomAD). c.76_92+27del44 has been reported in the literature in an individual affected with Beta Thalassemia who was compound heterozygous with another likely pathogenic variant (Gonzalez-Redondo_1989). These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 2753736). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014, and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

beta Thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

curation

The ITHANET community portal, The Cyprus Institute of Neurology and Genetics

Nov 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs63751076; hg19: chr11-5248132;