chr18-60371377-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM5BP4_Moderate
The NM_005912.3(MC4R):c.973C>A(p.Leu325Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. L325F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005912.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MC4R | NM_005912.3 | c.973C>A | p.Leu325Ile | missense_variant | 1/1 | ENST00000299766.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MC4R | ENST00000299766.5 | c.973C>A | p.Leu325Ile | missense_variant | 1/1 | NM_005912.3 | P1 | ||
ENST00000658928.1 | n.156+42032G>T | intron_variant, non_coding_transcript_variant | |||||||
ENST00000650201.1 | n.113+42032G>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251416Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135872
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727234
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74314
ClinVar
Submissions by phenotype
BODY MASS INDEX QUANTITATIVE TRAIT LOCUS 20 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 15, 2022 | The c.973C>A, p.Leu325Ile missense variant in MC4R has been reported in individuals with obesity [PMID:32952152]. The variant has been observed in thirty-seven alleles with no homozygotes in the population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8). This substitution occurs at a position that is moderately conserved across species, and in silico analysis predicts this variant is probably benign to the protein structure/function. Based on the available evidence, the variant c.973C>A, p.Leu325Ile in the MC4R gene is classified as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at