chr11-5226770-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PP3_ModerateBP6
The NM_000518.5(HBB):c.122G>A(p.Arg41Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,020 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. R41S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000518.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.122G>A | p.Arg41Lys | missense_variant | 2/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.122G>A | p.Arg41Lys | missense_variant | 2/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251398Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135858
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461866Hom.: 0 Cov.: 35 AF XY: 0.0000261 AC XY: 19AN XY: 727240
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74318
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 09, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 22, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 07, 2024 | Variant summary: HBB c.122G>A (p.Arg41Lys) results in a conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three 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 251398 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.122G>A has been reported in the literature as Hb-Athens-Georgia/Hb-Waco and has been associated with normal hematological parameters, a normal heme-heme interaction, normal Bohr effect, normal/reduced heme-heme interaction and increased oxygen affinity (example, Brown_1976, Moo-Penn_1977, Mrad_1989). It has recently been reported in a family with HbH disease resulting from alpha thalassemia deletions where the impact of this beta globin variant was not significant and a family member had normal hematological parameters with the authors concluding that this variant is non-pathological (example, Panyasai_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. The following publications have been ascertained in the context of this evaluation (PMID: 14597, 8114, 2757008, 33287582). ClinVar contains an entry for this variant (Variation ID: 15099). Based on the evidence outlined above, the variant was classified as likely benign. - |
HEMOGLOBIN ATHENS-GEORGIA Other:1
other, no assertion criteria provided | literature only | OMIM | Dec 12, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at