Genetic Variant NM_024592.5:c.50C>A (chr4-55346386-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024592.5(SRD5A3):c.50C>A(p.Ala17Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 1,422,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A17V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SRD5A3
NM_024592.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.313

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

SRD5A3-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia

SRD5A3 links:

ENSG00000288695 (HGNC:):

ENSG00000288695 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25352645).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024592.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A3	NM_024592.5	MANE Select	c.50C>A	p.Ala17Glu	missense	Exon 1 of 5	NP_078868.1	Q9H8P0
	SRD5A3	NM_001410732.1		c.50C>A	p.Ala17Glu	missense	Exon 1 of 4	NP_001397661.1	A0A7P0TBH6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SRD5A3	ENST00000264228.9	TSL:1 MANE Select	c.50C>A	p.Ala17Glu	missense	Exon 1 of 5	ENSP00000264228.4	Q9H8P0
ENSG00000288695	ENST00000679707.1		c.50C>A	p.Ala17Glu	missense	Exon 1 of 6	ENSP00000505713.1	A0A7P0T9P9
SRD5A3	ENST00000918496.1		c.50C>A	p.Ala17Glu	missense	Exon 1 of 5	ENSP00000588555.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000281

AC:

AN:

1422676

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705984

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30146

American (AMR)

AF:

0.00

AC:

AN:

40416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25094

East Asian (EAS)

AF:

0.00

AC:

AN:

35898

South Asian (SAS)

AF:

0.00

AC:

AN:

81848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49780

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5572

European-Non Finnish (NFE)

AF:

0.00000365

AC:

AN:

1095108

Other (OTH)

AF:

0.00

AC:

AN:

58814

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

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.32

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.55

M_CAP

Benign

0.041

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

0.31

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.2

REVEL

Benign

0.10

Sift

Benign

0.040

Sift4G

Benign

0.061

Polyphen

0.81

Vest4

0.38

MutPred

0.47

Loss of glycosylation at P14 (P = 0.0767)

MVP

0.43

MPC

0.60

ClinPred

0.71

GERP RS

2.9

PromoterAI

-0.025

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.25

gMVP

0.62

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over