rs33935673
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PP3_ModerateBP6
The NM_000518.5(HBB):āc.353A>Gā(p.His118Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,922 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H118P) has been classified as Likely benign.
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.353A>G | p.His118Arg | missense_variant | 3/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.353A>G | p.His118Arg | missense_variant | 3/3 | 1 | NM_000518.5 | P1 | |
HBB | ENST00000647020.1 | c.353A>G | p.His118Arg | missense_variant | 3/3 | P1 | |||
HBB | ENST00000475226.1 | n.285A>G | non_coding_transcript_exon_variant | 2/2 | 2 | ||||
HBB | ENST00000633227.1 | c.*169A>G | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152112Hom.: 0 Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461810Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727218
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152112Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74306
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 | Aug 14, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 21, 2023 | The HBB c.353A>G (p.His118Arg) variant has been reported in the published literature in heterozygous individuals or compound heterozygous with Hb C, as having normal to minimal clinical presentations (PMIDs: 1164567 (1975), 700140 (1978), and 6859036 (1983)). Additionally, it is reported as having normal stability and a minimally increased oxygen affinity. The frequency of this variant in the general population, 0.0000066 (1/152112 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 17, 2022 | Variant summary: HBB c.353A>G (p.His118Arg) variant, also known as HbP-Galveston, results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251276 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.353A>G has been reported in multiple individuals heterozygously and in compound heterozygosity with HbC or HbS and beta-thal variants. Compound hets patients showed minimal to no clinical features and hematological values were compared to b-thal, HbC or HbS carriers (Di Iorio_HBB_Blut_1975, Huisman_HBB_Febbs Lett_1978). At least one functional study showed that HbP does not differ significantly from WT (Hb A) with regard to oxygen affinity or stability (Di Iorio_HBB_Blut_1975). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at