chr2-31533663-A-C

Position:

• chr2-31533663-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000348.4(SRD5A2):​c.385T>G​(p.Tyr129Asp) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

Genes affected

SRD5A2 (HGNC:11285): (steroid 5 alpha-reductase 2) This gene encodes a microsomal protein expressed at high levels in androgen-sensitive tissues such as the prostate. The encoded protein is active at acidic pH and is sensitive to the 4-azasteroid inhibitor finasteride. Deficiencies in this gene can result in male pseudohermaphroditism, specifically pseudovaginal perineoscrotal hypospadias (PPSH). [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRD5A2	NM_000348.4	c.385T>G	p.Tyr129Asp	missense_variant	2/5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3	c.163T>G	p.Tyr55Asp	missense_variant	2/5		XP_011531371.1
SRD5A2	XM_011533072.3	c.130T>G	p.Tyr44Asp	missense_variant	4/7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2	c.385T>G	p.Tyr129Asp	missense_variant	2/5	1	NM_000348.4	ENSP00000477587	P1
	ENST00000435713.1	n.255+5963A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 08, 2017

This sequence change replaces tyrosine with aspartic acid at codon 129 of the SRD5A2 protein (p.Tyr129Asp). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and aspartic acid. In summary, this variant has uncertain impact on SRD5A2 function. The available evidence is currently insufficient to determine its role 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 do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15). This variant has not been reported in the literature in individuals with a SRD5A2-related disease. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Benign	0.90
FATHMM_MKL	Uncertain	0.89	D
MetaRNN	Pathogenic	0.85	D
PrimateAI	Benign	0.43	T
Sift4G	Uncertain	0.0080	D
Vest4		0.84
MVP		0.57
GERP RS		4.1
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553324169; hg19: chr2-31758733;