NM_024592.5:c.50C>T

Variant names:

• chr4-55346386-C-T
• rs1175656094
• NM_024592.5:c.50C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024592.5(SRD5A3):​c.50C>T​(p.Ala17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000127 in 1,574,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A17A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SRD5A3 NM_024592.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.313
• Publications: 0 publications found

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

ENSG00000288695 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042683303).

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>T	p.Ala17Val	missense	Exon 1 of 5	NP_078868.1	Q9H8P0
	SRD5A3	NM_001410732.1		c.50C>T	p.Ala17Val	missense	Exon 1 of 4	NP_001397661.1	A0A7P0TBH6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A3	ENST00000264228.9	TSL:1 MANE Select	c.50C>T	p.Ala17Val	missense	Exon 1 of 5	ENSP00000264228.4	Q9H8P0
	ENSG00000288695	ENST00000679707.1		c.50C>T	p.Ala17Val	missense	Exon 1 of 6	ENSP00000505713.1	A0A7P0T9P9
	SRD5A3	ENST00000918496.1		c.50C>T	p.Ala17Val	missense	Exon 1 of 5	ENSP00000588555.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422674 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 705982

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30146

American (AMR) AF: 0.00 AC: 0 AN: 40416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25094

East Asian (EAS) AF: 0.00 AC: 0 AN: 35898

South Asian (SAS) AF: 0.00 AC: 0 AN: 81848

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5572

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1095106

Other (OTH) AF: 0.00 AC: 0 AN: 58814

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74342

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	SRD5A3-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.89
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.31
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.040
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0080	B
Vest4		0.17
MutPred		0.24		Loss of glycosylation at P14 (P = 0.0767)
MVP		0.13
MPC		0.24
ClinPred		0.063	T
GERP RS		2.9
PromoterAI		-0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.054
gMVP		0.24
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1175656094; hg19: chr4-56212553;