chr22-42619904-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_000398.7(CYB5R3):c.775C>T(p.Arg259Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,607,638 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000398.7 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 | UniProt |
---|---|---|---|---|---|---|---|
CYB5R3 | NM_000398.7 | c.775C>T | p.Arg259Trp | missense_variant | 9/9 | ENST00000352397.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYB5R3 | ENST00000352397.10 | c.775C>T | p.Arg259Trp | missense_variant | 9/9 | 1 | NM_000398.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000164 AC: 25AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000421 AC: 10AN: 237464Hom.: 0 AF XY: 0.0000389 AC XY: 5AN XY: 128614
GnomAD4 exome AF: 0.0000220 AC: 32AN: 1455466Hom.: 1 Cov.: 32 AF XY: 0.0000194 AC XY: 14AN XY: 723386
GnomAD4 genome ? AF: 0.000164 AC: 25AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74346
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 259 of the CYB5R3 protein (p.Arg259Trp). This variant is present in population databases (rs139299188, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of methemoglobinemia (PMID: 28195434). This variant is also known as p.Arg258Trp. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYB5R3 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at