rs886039769
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_004959.5(NR5A1):c.274C>T(p.Arg92Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. R92Q) has been classified as Pathogenic.
Frequency
Consequence
NM_004959.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NR5A1 | NM_004959.5 | c.274C>T | p.Arg92Trp | missense_variant | 4/7 | ENST00000373588.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NR5A1 | ENST00000373588.9 | c.274C>T | p.Arg92Trp | missense_variant | 4/7 | 1 | NM_004959.5 | P1 | |
NR5A1 | ENST00000620110.4 | c.274C>T | p.Arg92Trp | missense_variant | 4/6 | 5 | |||
NR5A1 | ENST00000455734.1 | c.274C>T | p.Arg92Trp | missense_variant | 4/4 | 3 | |||
NR5A1 | ENST00000373587.3 | c.39+262C>T | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
46,XY sex reversal 3 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Shenzhen Institute of Pediatrics, Shenzhen Children's Hospital | Sep 30, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 23, 2021 | - - |
46,XX sex reversal 4 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Mar 23, 2016 | Likely pathogenicity based on finding it once in our study inferred de novo in a 31-year-old 46,XX male with hypogonadism, decreased testicular size, and primary testicular failure. This patient has been reported in PMID 27378692. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 23, 2021 | - - |
Oligosynaptic infertility;C2751824:46,XY disorder of sex development Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 16, 2021 | ClinVar contains an entry for this variant (Variation ID: 265792). This missense change has been observed in individual(s) with NR5A1-related conditions (PMID: 27378692, 27490115, 28033660). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 92 of the NR5A1 protein (p.Arg92Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NR5A1 function (PMID: 27378692). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 04, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at