4-55364153-C-CTA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_024592.5(SRD5A3):​c.445_446dupTA​(p.Val150ThrfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

SRD5A3
NM_024592.5 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.32
Variant links:
Genes affected
SRD5A3 (HGNC:25812): (steroid 5 alpha-reductase 3) The protein encoded by this gene belongs to the steroid 5-alpha reductase family, and polyprenol reductase subfamily. It is involved in the production of androgen 5-alpha-dihydrotestosterone (DHT) from testosterone, and maintenance of the androgen-androgen receptor activation pathway. This protein is also necessary for the conversion of polyprenol into dolichol, which is required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-linked glycosylation of proteins. Mutations in this gene are associated with congenital disorder of glycosylation type Iq. [provided by RefSeq, Mar 2011]
SRD5A3-AS1 (HGNC:44138): (SRD5A3 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-55364153-C-CTA is Pathogenic according to our data. Variant chr4-55364153-C-CTA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2630646.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SRD5A3NM_024592.5 linkc.445_446dupTA p.Val150ThrfsTer9 frameshift_variant Exon 3 of 5 ENST00000264228.9 NP_078868.1 Q9H8P0
SRD5A3NM_001410732.1 linkc.445_446dupTA p.Val150ThrfsTer9 frameshift_variant Exon 3 of 4 NP_001397661.1
SRD5A3XM_017008601.2 linkc.310_311dupTA p.Val105ThrfsTer9 frameshift_variant Exon 3 of 5 XP_016864090.1
SRD5A3XM_005265767.4 linkc.364+4666_364+4667dupTA intron_variant Intron 2 of 2 XP_005265824.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SRD5A3ENST00000264228.9 linkc.445_446dupTA p.Val150ThrfsTer9 frameshift_variant Exon 3 of 5 1 NM_024592.5 ENSP00000264228.4 Q9H8P0
ENSG00000288695ENST00000679707.1 linkc.445_446dupTA p.Val150ThrfsTer9 frameshift_variant Exon 3 of 6 ENSP00000505713.1 A0A7P0T9P9

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

SRD5A3-related disorder Pathogenic:1
Feb 27, 2023
PreventionGenetics, part of Exact Sciences
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The SRD5A3 c.445_446dupTA variant is predicted to result in a frameshift and premature protein termination (p.Val150Thrfs*9). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in SRD5A3 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-56230320; API