16-89919683-G-A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP4_StrongBS2
The NM_002386.4(MC1R):c.425G>A(p.Arg142His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,606,080 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MC1R | ENST00000555147.2 | c.425G>A | p.Arg142His | missense_variant | Exon 1 of 1 | 6 | NM_002386.4 | ENSP00000451605.1 | ||
ENSG00000198211 | ENST00000556922.1 | c.425G>A | p.Arg142His | missense_variant | Exon 1 of 5 | 2 | ENSP00000451560.1 | |||
MC1R | ENST00000555427.1 | c.425G>A | p.Arg142His | missense_variant | Exon 3 of 4 | 5 | ENSP00000451760.1 | |||
MC1R | ENST00000639847.1 | c.425G>A | p.Arg142His | missense_variant | Exon 3 of 3 | 5 | ENSP00000492011.1 |
Frequencies
GnomAD3 genomes AF: 0.00471 AC: 717AN: 152210Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00532 AC: 1298AN: 243850Hom.: 7 AF XY: 0.00523 AC XY: 694AN XY: 132602
GnomAD4 exome AF: 0.00646 AC: 9385AN: 1453752Hom.: 47 Cov.: 33 AF XY: 0.00629 AC XY: 4551AN XY: 723480
GnomAD4 genome AF: 0.00470 AC: 716AN: 152328Hom.: 1 Cov.: 33 AF XY: 0.00432 AC XY: 322AN XY: 74484
ClinVar
Submissions by phenotype
not provided Benign:6
The MC1R p.Arg142His variant was identified in dbSNP (ID: rs11547464) as "With Likely benign allele" and in ClinVar (classified as benign and likely benign by Invitae and Illumina, respectively; associated conditions are Cutaneous malignant melanoma 5 and Malignant Melanoma Susceptibility). The variant was not identified in Cosmic. The variant was also found in control databases in 1414 of 275224 chromosomes (7 homozygous) at a frequency of 0.005138 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 172 of 10318 chromosomes (freq: 0.01667), Other in 72 of 7130 chromosomes (freq: 0.0101), European (non-Finnish) in 874 of 127818 chromosomes (freq: 0.006838), Latino in 239 of 35340 chromosomes (freq: 0.006763), European (Finnish) in 27 of 19814 chromosomes (freq: 0.001363), African in 24 of 24718 chromosomes (freq: 0.000971), South Asian in 5 of 30578 chromosomes (freq: 0.000164), and East Asian in 1 of 19508 chromosomes (freq: 0.000051). The p.R142H variant is classified as a strong-R allele for the Red Hair Colour (RHC) phenotype (Morgan_2018_PMID: 30531825; Williams_2011_PMID: 21128237). The literature is inconsistent with regards to the p.R142H variant’s association with cutaneous melanoma (Williams_2011_PMID: 21128237; Artomov_2017_PMID: 29522175; Raimondi_2008_PMID: 18366057). One in vitro study showed the p.R142H variant has conserved binding properties but strongly impaired coupling to the cAMP generation system leading to red hair colour (Schioth_1999_PMID: 10403794). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg142 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
MC1R: PP3, BS2 -
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Melanoma, cutaneous malignant, susceptibility to, 5 Benign:2
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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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not specified Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at