rs368507952
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_002386.4(MC1R):c.917G>A(p.Arg306His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R306C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002386.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC1R | NM_002386.4 | c.917G>A | p.Arg306His | missense_variant | 1/1 | ENST00000555147.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC1R | ENST00000555147.2 | c.917G>A | p.Arg306His | missense_variant | 1/1 | NM_002386.4 | P1 | ||
ENST00000554623.1 | n.637C>T | non_coding_transcript_exon_variant | 2/2 | 3 | |||||
MC1R | ENST00000555427.1 | c.917G>A | p.Arg306His | missense_variant | 3/4 | 5 | |||
MC1R | ENST00000639847.1 | c.917G>A | p.Arg306His | missense_variant | 3/3 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000245 AC: 61AN: 248962Hom.: 0 AF XY: 0.000311 AC XY: 42AN XY: 135172
GnomAD4 exome AF: 0.000361 AC: 528AN: 1461654Hom.: 0 Cov.: 35 AF XY: 0.000385 AC XY: 280AN XY: 727110
GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152324Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74482
ClinVar
Submissions by phenotype
Melanoma, cutaneous malignant, susceptibility to, 5 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 08, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 306 of the MC1R protein (p.Arg306His). This variant is present in population databases (rs368507952, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with melanoma (PMID: 16982779, 19269164, 23312576, 23360207, 24982914). It has also been observed to segregate with oculocutaneous albinism in a single family (PMID: 23312576), but the clinical significance of this finding is uncertain. ClinVar contains an entry for this variant (Variation ID: 470716). 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 MC1R 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. - |
Tyrosinase-positive oculocutaneous albinism Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%) but quite commonly in the south asian population (0.1%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with MC1R- related disorder (PMID: 16645598). However, the evidence of pathogenicity is insufficient at this time and there are conflicting interpretations of pathogenicity (Clinvar ID: VCV000470716). Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at