rs63749819

Positions:

• chr11-5227001-CT-C

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.20delA​(p.Glu7fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,611,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: HBB NM_000518.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 0.690

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 located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 172 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5227001-CT-C is Pathogenic according to our data. Variant chr11-5227001-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 15418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227001-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.20delA	p.Glu7fs	frameshift_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.20delA	p.Glu7fs	frameshift_variant	1/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251184 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135734

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1459706 Hom.: 0 Cov.: 33 AF XY: 0.0000151 AC XY: 11 AN XY: 726338

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74382

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:5 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_000518.4(HBB):c.20delA(aka p.E7Gfs*13) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is a beta-zero variant associated with beta thalessemia. Sources cited for classification include the following: PMID 22271886 and 1734721. Classification of NM_000518.4(HBB):c.20delA(aka p.E7Gfs*13) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 20, 2016	Variant summary: The HBB c.20delA (p.Glu7Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. In addition, this region is known to be a mutational hot-spot. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.27dupG, c.36delT, c.46delT, etc.). This variant was found in 3/121348 control chromosomes at a frequency of 0.0000247, which is lower than the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). This variant is a known common pathogenic variant mainly reported in Algerian, Moroccan, and Sardinian populations in homozygous and/or heterozygous state. Additionally, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as a Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2023	The p.Glu7GlyfsX13 variant in HBB has been reported in >20 compound heterozygous or homozygous individuals with beta-thalassemia (Chang 1983 PMID: 6316272, Kazazian 1983 PMID: 6310991, Gonzalez-Redondo 1988 PMID: 2458145, Bouhass 1990 PMID: 2393712, Petkov 1990 PMID: 2200762, Economou 1991 PMID: 1769663, Baysal 1992 PMID: 1390250, Rosatelli 1992 PMID: 1734721, Vetter 1997 PMID: 9163586, Danjou 2012 PMID: 22271886). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 15418) and has been identified in 0.0048% (2/41456) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 7 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HBB gene is an established disease mechanism in autosomal recessive beta thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive beta-thalassemia. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PM2_Supporting. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2022	Observed multiple times in published literature in individuals with Beta-Thalassemia; however detailed clinical information and segregation was not provided (Economou et al., 1991; Rosatelli et al., 1992; Baysal et al 1992; Gonzalez-Redondo et al., 1988; Kazazian et al., 1983); Frameshift 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; This variant is associated with the following publications: (PMID: 27785405, 6310991, 9163586, 34662886, 22975760, 26956563, 1390250, 8262525, 1734721, 17486495, 2458145, 1769663) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2023	The HBB c.20delA; p.Glu7fs variant (also known as Glu6fs when numbered from the mature protein or as Codon 6 (-A), rs63749819, HbVar ID: 784) has been reported in multiple individuals with beta(0) thalassemia (Bouhass 1990, Gonzalez-Redondo 1988, Kazazian 1983, Rosatelli 1992, HbVar database and references therein). This variant is found in the general population with an overall allele frequency of 0.002% (4/251184 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database for Codon 6 (-A): https://globin.bx.psu.edu/hbvar/hbvar.html Bouhass R et al. A new mutation at IVS1 nt 2(T----A), in beta-thalassemia from Algeria. Blood. 1990; 76(5):1054-5. PMID: 2393712. Kazazian HH Jr et al. beta-Thalassemia due to a deletion of the nucleotide which is substituted in the beta S-globin gene. Am J Hum Genet. 1983; 35(5):1028-33. PMID: 6310991. Gonzalez-Redondo J et al. Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. Blood. 1988; 72(3):1007-14. PMID: 2458145. Rosatelli M et al. Molecular characterization of beta-thalassemia in the Sardinian population. Am J Hum Genet. 1992; 50(2):422-6. PMID: 1734721. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Glu7Glyfs*13) 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 (rs63749819, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with β-thalassemia (PMID: 6310991). This variant is also known as deletion of A in codon 6 of the beta gene. ClinVar contains an entry for this variant (Variation ID: 15418). For these reasons, this variant has been classified as Pathogenic. -

Beta zero thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1993

- -

Beta-thalassemia HBB/LCRB Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Feb 01, 2024

- -

alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 20, 2022

- -

Hb SS disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

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: rs63749819; hg19: chr11-5248231;