rs33941849

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_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

Scores

8
5
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.93
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 90 pathogenic variants. Next in-frame start position is after 165 CDS bases. Genomic position: 5226727. Lost 0.372 part of the original CDS.
PS1
Another start lost variant in NM_000518.5 (HBB) was described as [Pathogenic] in Lovd
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 rank MANE Protein UniProt
HBBNM_000518.5 linkc.2T>G p.Met1? start_lost Exon 1 of 3 ENST00000335295.4 NP_000509.1 P68871D9YZU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBBENST00000335295.4 linkc.2T>G p.Met1? start_lost Exon 1 of 3 1 NM_000518.5 ENSP00000333994.3 P68871

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
show subpopulations
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:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

beta Thalassemia Pathogenic:4
Oct 05, 2017
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 25, 2019
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: curation

- -

Mar 17, 2017
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 14, 2020
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not provided Pathogenic:3
Sep 01, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. This variant is also known as CD0T>G, Initiation codon ATG‚ÜíAGG. ClinVar contains an entry for this variant (Variation ID: 15434). 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. For these reasons, this variant has been classified as Pathogenic. 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. -

Dec 29, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The HBB c.2T>G; p.Met1? variant (rs33941849, HbVar ID: 777) is reported in the literature in individuals affected with beta(0) thalassemia, with no detectable expression of the beta globin protein in a patient possessing a beta(0) thalassemia variant on the other chromosome (HbVar database and references therein). This variant is reported in ClinVar (Variation ID: 15434), and is absent from the Genome Aggregation Database (v2.1.1), 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 database: https://globin.bx.psu.edu/hbvar/menu.html -

Oct 06, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Jun 01, 1992
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

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
May 29, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hb SS disease Pathogenic:1
-
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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
LIST_S2
Uncertain
0.90
.;D;D;D
M_CAP
Pathogenic
0.88
D
MetaRNN
Pathogenic
0.92
D;D;D;D
MetaSVM
Uncertain
0.78
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs33941849; hg19: chr11-5248250; API