11-5225632-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate
The NM_000518.5(HBB):c.410G>A(p.Gly137Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,996 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137A) has been classified as Pathogenic.
Frequency
Consequence
NM_000518.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.410G>A | p.Gly137Asp | missense_variant | 3/3 | ENST00000335295.4 | NP_000509.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.410G>A | p.Gly137Asp | missense_variant | 3/3 | 1 | NM_000518.5 | ENSP00000333994.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251372Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135866
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461820Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727230
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74354
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 24, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 02, 2024 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 26, 2022 | Variant summary: HBB c.410G>A (p.Gly137Asp) results in a non-conservative amino acid change located in the globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251372 control chromosomes (gnomAD). c.410G>A has been reported in the literature as a clinically innocuous variant in individuals with mildly anemic phenotypes and also in co-occurrence among individuals with HbCS, Hb-H disease, and HbE/beta-thalassemia (e.g. Minnich_1965, Ingle_2004, Enoki_1989, Martinez_1984, Pagnier_1978, Sura_2007, Beneitez_2006, Fucharoen_2012, Svasti_2001, Chunpanich_2004, Rahbar_1992, Pillers_1992, Delacour_2016, Srivorakun_2014, Singha_2021). In particular, compound heterozygous individuals with Hb-Hope-HbS genotypes did not present with sickle cell disease phenotype (e.g. Ingle_2004). These data indicate that the variant is not strongly associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Enoki_1989). The most pronounced variant effect results in reduced oxygen affinity. Three clinical diagnostic laboratories and OMIM have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Most classified the variant as benign/likely benign, and one laboratory classified it as VUS. Based on the evidence outlined above, the variant was classified as likely benign. - |
Benign, no assertion criteria provided | literature only | OMIM | Dec 12, 2017 | - - |
Hb SS disease Pathogenic:1
Pathogenic, flagged submission | clinical testing | Baylor Genetics | - | - - |
Beta-thalassemia HBB/LCRB Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 08, 2017 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
beta Thalassemia Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at