rs145712014

Variant names:

• chr2-31526227-G-T
• rs145712014
• NM_000348.4:c.734C>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000348.4(SRD5A2):​c.734C>A​(p.Ser245Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000138 in 1,590,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: SRD5A2 NM_000348.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.81

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022504747).
• BP6: Variant 2-31526227-G-T is Benign according to our data. Variant chr2-31526227-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436858.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4	c.734C>A	p.Ser245Tyr	missense_variant	Exon 5 of 5	ENST00000622030.2	NP_000339.2
SRD5A2	XM_011533069.3	c.512C>A	p.Ser171Tyr	missense_variant	Exon 5 of 5		XP_011531371.1
SRD5A2	XM_011533072.3	c.479C>A	p.Ser160Tyr	missense_variant	Exon 7 of 7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2	c.734C>A	p.Ser245Tyr	missense_variant	Exon 5 of 5	1	NM_000348.4	ENSP00000477587.1

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000200 AC: 43 AN: 215076 Hom.: 0 AF XY: 0.000165 AC XY: 19 AN XY: 115342

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.000128

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000614

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000904 AC: 130 AN: 1438136 Hom.: 0 Cov.: 28 AF XY: 0.0000870 AC XY: 62 AN XY: 712946

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.000119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000560

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.000151

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74482

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000949 Hom.: 0

Bravo AF: 0.000714

ESP6500AA AF: 0.00220 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000274 AC: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Jan 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in an individual from a 5-alpha-reductase deficiency cohort, however, it is unknown if this was seen in the homozygous state or with a second SRD5A2 variant (PMID: 32380235); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21604088, 32380235, 33469028, 10718838) -

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

Oct 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Benign	0.85
FATHMM_MKL	Uncertain	0.94	D
MetaRNN	Benign	0.023	T
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	0.57	T
Vest4		0.44
MVP		0.60
GERP RS		4.9
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs145712014; hg19: chr2-31751297;