4-55364153-C-CTA

Variant names:

• chr4-55364153-C-CTA
• NM_024592.5:c.445_446dupTA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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 (★). Synonymous variant affecting the same amino acid position (i.e. Y149Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRD5A3 NM_024592.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.32
• Publications: 0 publications found

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]

ENSG00000288695 (HGNC:):

SRD5A3-AS1 (HGNC:44138): (SRD5A3 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 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
SRD5A3	NM_024592.5	c.445_446dupTA	p.Val150ThrfsTer9	frameshift_variant	Exon 3 of 5	ENST00000264228.9	NP_078868.1
SRD5A3	NM_001410732.1	c.445_446dupTA	p.Val150ThrfsTer9	frameshift_variant	Exon 3 of 4		NP_001397661.1
SRD5A3	XM_017008601.2	c.310_311dupTA	p.Val105ThrfsTer9	frameshift_variant	Exon 3 of 5		XP_016864090.1
SRD5A3	XM_005265767.4	c.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
SRD5A3	ENST00000264228.9	c.445_446dupTA	p.Val150ThrfsTer9	frameshift_variant	Exon 3 of 5	1	NM_024592.5	ENSP00000264228.4
ENSG00000288695	ENST00000679707.1	c.445_446dupTA	p.Val150ThrfsTer9	frameshift_variant	Exon 3 of 6			ENSP00000505713.1

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

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
PhyloP100		3.3

Splicing

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

Other links and lift over

hg19: chr4-56230320;