rs34484056
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000518.5(HBB):c.341T>A(p.Val114Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,998 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
HBB
NM_000518.5 missense
NM_000518.5 missense
Scores
9
4
5
Clinical Significance
Conservation
PhyloP100: 1.68
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in NM_000518.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.878
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.341T>A | p.Val114Glu | missense_variant | 3/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.341T>A | p.Val114Glu | missense_variant | 3/3 | 1 | NM_000518.5 | P1 | |
HBB | ENST00000647020.1 | c.341T>A | p.Val114Glu | missense_variant | 3/3 | P1 | |||
HBB | ENST00000475226.1 | n.273T>A | non_coding_transcript_exon_variant | 2/2 | 2 | ||||
HBB | ENST00000633227.1 | c.*157T>A | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251270Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135808
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461796Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727212
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 17, 2023 | The Hb New York variant (HBB: c.341T>A; p.Val114Glu, also known as Val113Glu when numbered from the mature protein, HbVar ID: 491) is reported in the heterozygous state in individuals with no associated hematological symptoms, and did not affect clinical symptoms when occurring in-trans with beta thalassemia or hemoglobin E, or when coinherited with alpha thalassemia trait (Chaibunruang 2018, Ranney 1967, Todd 1980, HbVar database and references therein). However, this variant is reported to contribute to a clinically significant sickling disorder in individuals who also carry the hemoglobin S allele (Calder 2012, McFarlane 2011). This variant is reported in ClinVar (Variation ID: 15286), and is only observed on six alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 114 is highly conserved, and results in a mildly unstable variant protein and reduced oxygen affinity (HbVar database and references therein). Based on available information, the Hb New York variant is considered likely pathogenic for sickling disease when found with HbS, although there is no evidence that it is disease-associated alone or in trans with a beta-thalassemia variant. References: Link to HbVar for HB New York: https://globin.bx.psu.edu/hbvar/menu.html Calder D et al. Sickle retinopathy in a person with hemoglobin s/new york disease. Case Rep Genet. 2012;2012:136582. PMID: 23346429. Chaibunruang A et al. Molecular Characteristics of Hb New York (B113(G15)Val?Glu, HBB: c.341T>A) in Thailand. Hemoglobin. 2018 Jan;42(1):11-15. PMID: 29464999. McFarlane A et al. A novel sickling hemoglobinopathy. N Engl J Med. 2011 Oct 20;365(16):1548-9. PMID: 22010933. Ranney HM et al. Haemoglobin New York. Nature. 1967 Mar 4;213(5079):876-8. PMID: 6030043. Todd D et al. Globin chain synthesis in haemoglobin New York (beta 113 replaced by glutamic acid). Br J Haematol. 1980 Dec;46(4):557-64. PMID: 7437334. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2022 | Reported in unrelated patients with features of sickle cell trait; however, these patients also harbored the c.20A>T common variant (McFarlane et al., 2011; Calder et al., 2012); Also observed in patients referred for carrier screening and have normal hemoglobin testing (Lin et al., 2013; van Zwieten et al., 2014; Lou et al., 2014; Huang et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Hb New York or Hb Kaohsiung; This variant is associated with the following publications: (PMID: 24200101, 24099628, 1428942, 12403232, 28865746, 24055728, 19631632, 18432506, 1634358, 25089872, 31980563, 29626415, 36053226, 22010933, 19429541, 30837609, 29464999, 28143837, 24985555, 23346429, 23383304) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 13, 2023 | - - |
not specified Pathogenic:1Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1980 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 27, 2021 | Variant summary: HBB c.341T>A (p.Val114Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00051 in 630098 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (0.00051 vs 0.011), allowing no conclusion about variant significance. Compound heterozygotes of c.341T>A and a beta thalassmia mutation have been reported in the literature in individuals affected with sickling disorder symptoms (McFarlane_2011). However, similar compound heterozygotes have been reported in patients without significant clinical symptoms (Zeng_1982, Lee_2008). In addition, compound heterozygotes of c.341T>A and an alpha-thalassemia allele have also been reported in patients without significant clinical symptoms (Ranney_1967, Chaibunruang_2018). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Uncertain
D;.
Polyphen
D;D
Vest4
MutPred
Gain of catalytic residue at V114 (P = 0.0981);Gain of catalytic residue at V114 (P = 0.0981);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at