4-55346338-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_024592.5(SRD5A3):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,488,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SRD5A3
NM_024592.5 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.693

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SRD5A3	NM_024592.5 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/5	ENST00000264228.9
SRD5A3	NM_001410732.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/4
SRD5A3	XM_005265767.4 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A3	ENST00000264228.9 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/5	1	NM_024592.5	P1
SRD5A3	ENST00000679836.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/4

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152078

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000220

AC:

AN:

90894

Hom.:

AF XY:

0.00

AC XY:

AN XY:

51344

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000319

Gnomad OTH exome

AF:

0.000425

GnomAD4 exome

AF:

0.0000112

AC:

AN:

1336172

Hom.:

Cov.:

AF XY:

0.0000122

AC XY:

AN XY:

658358

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000114

Gnomad4 OTH exome

AF:

0.0000182

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000383

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

SRD5A3-congenital disorder of glycosylation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Kahrizi syndrome;C4317224:SRD5A3-congenital disorder of glycosylation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.020

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.083

Eigen

Benign

0.15

Eigen_PC

Benign

0.065

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.99

MetaSVM

Benign

-0.80

MutationTaster

Benign

1.0

PROVEAN

Benign

-0.91

REVEL

Uncertain

0.37

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.032

Polyphen

0.93

Vest4

0.70

MutPred

1.0

Loss of glycosylation at P3 (P = 0.0399);

MVP

0.66

ClinPred

0.99

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.94

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over