rs63750532

chr11-5226779-CA-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.112del(p.Trp38GlyfsTer24) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HBB NM_000518.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 5.72

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 254 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5226779-CA-C is Pathogenic according to our data. Variant chr11-5226779-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 15431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226779-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.112del	p.Trp38GlyfsTer24	frameshift_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.112del	p.Trp38GlyfsTer24	frameshift_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461862 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	The p.Trp38GlyfsX24 (c.112delT or "36/37(-T)") variant in HBB has been reported in over 30 individuals with beta thalassemia (Yılmaz 2019 PMID: 31411089, Yavarian 2001 PMID: 11300348, Tekes 2022, Rund 1991 PMID: 1986379, Moradi 2020 PMID: 32869674, Kiani 2007 PMID: 17654071, Jalilian 2017 PMID: 28391758, Guzelgul 2020 PMID: 32664780, Amin 2020 PMID: 33335418). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 15431). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 38 and leads to a premature termination codon 24 amino acids downstream. This is 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, PS4, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 09, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 15431). This variant is also known as nonsense 39. This premature translational stop signal has been observed in individual(s) with beta thalassemia (PMID: 1986379, 28391758). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp38Glyfs*24) 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 submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 07, 2021	The HBB c.112delT; p.Trp38fs variant (rs63750532), also known as Codons 36/37 (-T) or Frameshift 36/37, is described in the literature in individuals with thalassemia who also carried another pathogenic variant (Rund 1991). This variant is reported as pathogenic in ClinVar (15431). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. 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 c.112delT variant in HbVar: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=840&.cgifields=histD Rund D et al. Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan. Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):310-4. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 28, 2021	The HBB c.112del (p.Trp38Glyfs*24) 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 has been reported in individuals with beta thalassemia (PMIDs: 32190157 (2020), 2197725 (1990), 1986379 (1991) 28391758 (2017), 31134759 (2019), 26084319 (2015)). Previous names for this variant include Codons 36/37 (-T) and CCT TGG (Pro-Trp). Based on the available information, this variant is classified as pathogenic. -

Beta zero thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1991

- -

Hemoglobinopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 09, 2018

Variant summary: The HBB c.112delT (p.Trp38GlyfsX24) 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. This variant is absent in 30964 control chromosomes (gnomAD). Multiple publications have cited the variant in individuals affected with BTHAL, observed predominantly in middle eastern countries (Rund_1991, El-Kalla_1997, Huisman_1997). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:Methemoglobinemia, beta-globin 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 13, 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: rs63750532; hg19: chr11-5248009;