NM_024592.5:c.506A>G
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_024592.5(SRD5A3):āc.506A>Gā(p.Tyr169Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,976 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024592.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SRD5A3 | NM_024592.5 | c.506A>G | p.Tyr169Cys | missense_variant | Exon 3 of 5 | ENST00000264228.9 | NP_078868.1 | |
SRD5A3 | NM_001410732.1 | c.506A>G | p.Tyr169Cys | missense_variant | Exon 3 of 4 | NP_001397661.1 | ||
SRD5A3 | XM_017008601.2 | c.371A>G | p.Tyr124Cys | missense_variant | Exon 3 of 5 | XP_016864090.1 | ||
SRD5A3 | XM_005265767.4 | c.364+4727A>G | intron_variant | Intron 2 of 2 | XP_005265824.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SRD5A3 | ENST00000264228.9 | c.506A>G | p.Tyr169Cys | missense_variant | Exon 3 of 5 | 1 | NM_024592.5 | ENSP00000264228.4 | ||
ENSG00000288695 | ENST00000679707.1 | c.506A>G | p.Tyr169Cys | missense_variant | Exon 3 of 6 | ENSP00000505713.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152088Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251460Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135904
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727244
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152088Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74274
ClinVar
Submissions by phenotype
SRD5A3-congenital disorder of glycosylation Pathogenic:1Uncertain:1
This novel homozygous variant has been identified in a proband with global developmental delay, deep set eyes, nystagmus, bilateral epicanthal folds, temporal balding, flapping of hands, happy demeanor, self absorbed. This variant has been identified in 0.0028% in gnomAD (aggregated) (PM2_moderate). -
This sequence change in SRD5A3 is predicted to replace tyrosine with cysteine at codon 169, p.(Tyr169Cys). The tyrosine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the 3-oxo-5-alpha-steroid 4-dehydrogenase C-terminal domain. There is a large physicochemical difference between tyrosine and cysteine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.009% (8/91,080 alleles) in the South Asian population, consistent with recessive disease. This variant has been detected as homozygous in at least four individuals with a phenotype consistent with SRD5A3-congenital disorder of glycosylation and segregates with disease in two families (PMID: 21937992; doi: https://doi.org/10.1101/2024.01.08.23299914; ClinVar: SCV003935142.1; this individual). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.664) and predicts no impact on splicing (SpliceAI) for the nucleotide change. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2_Supporting, PM3, PP1_Strong, PP3. -
Kahrizi syndrome Pathogenic:1
- -
not provided Uncertain:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21937992) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at