rs33941849

chr11-5227020-A-Cchr11-5227020-A-Gchr11-5227020-A-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000518.5(HBB):c.2T>G(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HBB NM_000518.5 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.93

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000518.5 (HBB) was described as [Pathogenic] in ClinVar as 869315
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5227020-A-C is Pathogenic according to our data. Variant chr11-5227020-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 15434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5227020-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.2T>G	p.Met1?	start_lost	1/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.2T>G	p.Met1?	start_lost	1/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1441946 Hom.: 0 Cov.: 26 AF XY: 0.00000139 AC XY: 1 AN XY: 718728

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:4

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 14, 2020	Variant summary: HBB c.2T>G (p.Met1Arg) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Arginine is not a known alternative start codon for eukaryotes in nature; thus, translation would be predicted to start at the next Met in the HBB protein (which is at amino acid 56), causing a loss of translation of the normal N-terminus of the protein. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251128 control chromosomes (gnomAD). c.2T>G has been reported in the literature in multiple individuals affected with Beta Thalassemia (e.g. Lam_1990, Lee_2002, Su_2003). 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. This codon is in a mutational hotspot where other changes [such as: p.M1I (c.3G>A, C, and T), p.M1L, p.M1K, p.M1T and p.M1V] at the same residue have also been found in HBB patients (source: HGMD). Four ClinVar submitters (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	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 05, 2017	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the HBB mRNA. The next in-frame methionine is located at codon 56. Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal recessive beta thalassemia (PMID: 12955718, 14715623, 29695942). This variant has been reported in individual(s) with autosomal dominant beta thalassemia (PMID: 8144357); however, the role of the variant in this condition is currently unclear. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the HBB protein in which other variant(s) (p.Glu7Lys) have been determined to be pathogenic (PMID: 20301551, 23297836, 26372199, 27117572). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 15434). This variant is also known as CD0T>G, Initiation codon ATG‚ÜíAGG. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2019	The HBB c.2T>G; p.Met1? variant (rs33941849) is reported in the literature in individuals affected with beta(0) thalassemia (HbVar database), with no detectable expression of the beta globin protein in a patient possessing a beta(0) thalassemia variant on the other chromosome (Lam 1990). This variant is reported in ClinVar (Variation ID: 15434), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant ablates the canonical translation initiation codon, and is predicted to lead to an aberrant or absent protein. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar for c.2T>G: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=777 Lam V et al. A new single nucleotide change at the initiation codon (ATG----AGG) identified in amplified genomic DNA of a Chinese beta-thalassemic patient. Blood. 1990 75(5):1207-8. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 06, 2021	This variant disrupts in the translation initiation codon of the HBB mRNA and is predicted to interfere with HBB protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is associated with beta-zero-thalassemia and is known to be a common Chinese beta-thalassemia pathogenic variant (PMID: 2306523 (1990), 27829298 (2016), 34474730 (2021), 34293487 (2021)). Based on the available information, this variant is classified as pathogenic. -

Beta zero thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1992

- -

Hb SS disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Benign	0.17	T;T;.;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationTaster	Benign	1.0	D
PROVEAN	Uncertain	-3.1	D;.;.;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		0.99	D;D;.;.
Vest4		0.88
MutPred		0.64		Gain of methylation at M1 (P = 0.0281);Gain of methylation at M1 (P = 0.0281);Gain of methylation at M1 (P = 0.0281);Gain of methylation at M1 (P = 0.0281);
MVP		0.87
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.85

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: rs33941849; hg19: chr11-5248250;