rs35117167
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000335295.4(HBB):c.437A>G(p.Tyr146Cys) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y146H) has been classified as Pathogenic.
Frequency
Consequence
ENST00000335295.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.437A>G | p.Tyr146Cys | 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.437A>G | p.Tyr146Cys | missense_variant | 3/3 | 1 | NM_000518.5 | ENSP00000333994 | P1 | |
HBB | ENST00000647020.1 | c.437A>G | p.Tyr146Cys | missense_variant | 3/3 | ENSP00000494175 | P1 | |||
HBB | ENST00000633227.1 | c.*253A>G | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 3 | ENSP00000488004 | ||||
HBB | ENST00000475226.1 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 21, 2020 | The Hb Rainier variant (HBB: c.437A>G; p.Tyr146Cys, also known as Tyr145Cys when numbered from the mature protein, rs35117167) is reported in the literature in the heterozygous state in multiple individuals affected with erythrocytosis (see link to HbVar and references therein, Adamson 1969). This variant is reported in ClinVar (Variation ID: 15322), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 146 is highly conserved, and functional analyses of the variant protein show increased oxygen affinity (see link to HbVar, Adamson 1969). Additionally, other amino acid substitutions at this codon (Hb Nancy, Hb Osler, Hb Bethesda, Hb McKees Rocks) have been reported in individuals with erythrocytosis and are considered pathogenic (HbVar IDs: 570, 572, 573, 574), and several hemoglobin variants with high oxygen affinity leading to erythrocytosis are located at the carboxy-terminal end of the HBB gene (Wajcman 2004). Based on available information, the Hb Rainier variant is considered to be pathogenic. References: Link to HbVar for Hb Rainier: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=571 Adamson JW et al. Erythrocytosis associated with hemoglobin Rainier: oxygen equilibria and marrow regulation. J Clin Invest. 1969 Aug;48(8):1376-86. Wajcman H and Galacteros F. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin. 2005;29(2):91-106. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 11, 2019 | Not found in the total gnomAD dataset, and the data is high quality. Conflicting predictions of the effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. - |
Erythrocytosis, familial, 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1999 | - - |
HEMOGLOBIN RAINIER 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