NM_000348.4:c.358A>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1PM2PP2PP5_Very_StrongBP4

The NM_000348.4(SRD5A2):c.358A>C(p.Thr120Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,585,634 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SRD5A2
NM_000348.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: -0.186

Publications

1 publications found

Variant links:

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]

SRD5A2 Gene-Disease associations (from GenCC):

46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

SRD5A2 links:

ENSG00000228563 (HGNC:):

ENSG00000228563 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a chain 3-oxo-5-alpha-steroid 4-dehydrogenase 2 (size 253) in uniprot entity S5A2_HUMAN there are 48 pathogenic changes around while only 12 benign (80%) in NM_000348.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 40 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Trascript score misZ: -0.88748 (below the threshold of 3.09). GenCC associations: The gene is linked to 46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency.

PP5

Variant 2-31533690-T-G is Pathogenic according to our data. Variant chr2-31533690-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 582210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.2507316). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4 link	c.358A>C	p.Thr120Pro	missense_variant	Exon 2 of 5	ENST00000622030.2	NP_000339.2	P31213
SRD5A2	XM_011533069.3 link	c.136A>C	p.Thr46Pro	missense_variant	Exon 2 of 5		XP_011531371.1
SRD5A2	XM_011533072.3 link	c.103A>C	p.Thr35Pro	missense_variant	Exon 4 of 7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030.2 link	c.358A>C	p.Thr120Pro	missense_variant	Exon 2 of 5	1	NM_000348.4	ENSP00000477587.1		P31213
ENSG00000228563	ENST00000435713.1 link	n.255+5990T>G		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000482

AC:

AN:

207500

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000279

AC:

AN:

1433416

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710002

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32986

American (AMR)

AF:

0.00

AC:

AN:

40644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25544

East Asian (EAS)

AF:

0.00

AC:

AN:

38476

South Asian (SAS)

AF:

0.00

AC:

AN:

81406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51852

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00000365

AC:

AN:

1097318

Other (OTH)

AF:

0.00

AC:

AN:

59452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency

Pathogenic:2

Nov 20, 2023

Clinical Biochemistry Laboratory, Health Services Laboratory

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG:PS5 PM2 PM3 PP4 PP5 -

Mar 22, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SRD5A2 protein function. ClinVar contains an entry for this variant (Variation ID: 582210). This missense change has been observed in individuals with 5-alpha-reductase deficiency (PMID: 21402750). This variant is present in population databases (rs764433016, gnomAD 0.001%). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 120 of the SRD5A2 protein (p.Thr120Pro). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Benign

(source)

DANN

Benign

0.64

FATHMM_MKL

Benign

0.047

MetaRNN

Benign

0.25

PhyloP100

-0.19

PrimateAI

Benign

0.21

Sift4G

Benign

0.078

Vest4

0.34

MVP

0.46

GERP RS

-11

gMVP

0.77

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_000348.4:c.358A>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over