19-2250676-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_ModeratePM2PP3_Moderate
The NM_000479.5(AMH):c.580C>T(p.Arg194Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,539,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.
Frequency
Consequence
NM_000479.5 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AMH | NM_000479.5 | c.580C>T | p.Arg194Cys | missense_variant | Exon 3 of 5 | ENST00000221496.5 | NP_000470.3 | |
MIR4321 | NR_036207.1 | n.38C>T | non_coding_transcript_exon_variant | Exon 1 of 1 | ||||
MIR4321 | unassigned_transcript_3189 | n.-12C>T | upstream_gene_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AMH | ENST00000221496.5 | c.580C>T | p.Arg194Cys | missense_variant | Exon 3 of 5 | 1 | NM_000479.5 | ENSP00000221496.2 | ||
AMH | ENST00000589313.2 | n.933C>T | non_coding_transcript_exon_variant | Exon 1 of 3 | 5 | |||||
MIR4321 | ENST00000592276.1 | n.38C>T | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 | |||||
AMH | ENST00000592877.1 | n.461C>T | non_coding_transcript_exon_variant | Exon 2 of 2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152216Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000146 AC: 2AN: 137028Hom.: 0 AF XY: 0.0000268 AC XY: 2AN XY: 74712
GnomAD4 exome AF: 0.0000123 AC: 17AN: 1387464Hom.: 0 Cov.: 35 AF XY: 0.0000146 AC XY: 10AN XY: 684840
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152216Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74354
ClinVar
Submissions by phenotype
not provided Uncertain:1
Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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. Experimental studies have shown that this missense change affects AMH function (PMID: 14673134). This missense change has been observed in individual(s) with persistent Mullerian duct syndrome (PMID: 8162013). While this variant is present in population databases (rs777003373), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with cysteine at codon 194 of the AMH protein (p.Arg194Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at