rs772795484
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_024592.5(SRD5A3):c.436G>A(p.Glu146Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,034 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.436G>A | p.Glu146Lys | missense_variant | Exon 3 of 5 | ENST00000264228.9 | NP_078868.1 | |
SRD5A3 | NM_001410732.1 | c.436G>A | p.Glu146Lys | missense_variant | Exon 3 of 4 | NP_001397661.1 | ||
SRD5A3 | XM_017008601.2 | c.301G>A | p.Glu101Lys | missense_variant | Exon 3 of 5 | XP_016864090.1 | ||
SRD5A3 | XM_005265767.4 | c.364+4657G>A | 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.436G>A | p.Glu146Lys | missense_variant | Exon 3 of 5 | 1 | NM_024592.5 | ENSP00000264228.4 | ||
ENSG00000288695 | ENST00000679707.1 | c.436G>A | p.Glu146Lys | missense_variant | Exon 3 of 6 | ENSP00000505713.1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251466Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135906
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727246
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74324
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); 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: 31589614, 31638560) -
SRD5A3-congenital disorder of glycosylation Uncertain:1
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. 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. ClinVar contains an entry for this variant (Variation ID: 424422). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1q (PMID: 31638560). This variant is present in population databases (rs772795484, gnomAD 0.004%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 146 of the SRD5A3 protein (p.Glu146Lys). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at