rs34868397
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_000518.5(HBB):c.134C>G(p.Ser45Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. S45S) 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.134C>G | p.Ser45Cys | missense_variant | 2/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.134C>G | p.Ser45Cys | missense_variant | 2/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1978 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 09, 2021 | The Hb Mississippi variant (HBB: c.134C>G; p.Ser45Cys, also known as Ser44Cys when numbered from the mature protein, rs34868397) is reported to be a mildly unstable hemoglobin variant. Hb Mississippi heterozygotes are clinically and hematologically normal, however, Hb Mississippi in trans to a Beta(+)-thalassemia allele is reported to cause a thalassemia intermedia phenotype (Steinberg 1987). The Hb Mississippi variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 45 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.711). However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES HbVar link to Hb Mississippi: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=319&.cgifields=histD Steinberg MH et al. Hemoglobin Mississippi (beta 44ser----cys). Studies of the thalassemic phenotype in a mixed heterozygote with beta +-thalassemia. J Clin Invest. 1987 Mar;79(3):826-32. PMID: 2434529. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at