rs376780075
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_002386.4(MC1R):c.686G>A(p.Arg229His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,611,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_002386.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MC1R | ENST00000555147.2 | c.686G>A | p.Arg229His | missense_variant | Exon 1 of 1 | 6 | NM_002386.4 | ENSP00000451605.1 | ||
ENSG00000198211 | ENST00000556922.1 | c.686G>A | p.Arg229His | missense_variant | Exon 1 of 5 | 2 | ENSP00000451560.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000244 AC: 6AN: 245480Hom.: 0 AF XY: 0.0000374 AC XY: 5AN XY: 133566
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1459126Hom.: 0 Cov.: 35 AF XY: 0.0000248 AC XY: 18AN XY: 725938
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74364
ClinVar
Submissions by phenotype
Melanoma, cutaneous malignant, susceptibility to, 5 Uncertain:1
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 not expected to disrupt MC1R protein function. ClinVar contains an entry for this variant (Variation ID: 239160). This variant has not been reported in the literature in individuals affected with MC1R-related conditions. This variant is present in population databases (rs376780075, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 229 of the MC1R protein (p.Arg229His). 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