4-55364099-C-G

Variant names:

• chr4-55364099-C-G
• rs1719785978
• NM_024592.5:c.390C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024592.5(SRD5A3):​c.390C>G​(p.Phe130Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRD5A3 NM_024592.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.223

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]

ENSG00000288695 (HGNC:):

SRD5A3-AS1 (HGNC:44138): (SRD5A3 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0659101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A3	NM_024592.5	c.390C>G	p.Phe130Leu	missense_variant	Exon 3 of 5	ENST00000264228.9	NP_078868.1
SRD5A3	NM_001410732.1	c.390C>G	p.Phe130Leu	missense_variant	Exon 3 of 4		NP_001397661.1
SRD5A3	XM_017008601.2	c.255C>G	p.Phe85Leu	missense_variant	Exon 3 of 5		XP_016864090.1
SRD5A3	XM_005265767.4	c.364+4611C>G		intron_variant	Intron 2 of 2		XP_005265824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A3	ENST00000264228.9	c.390C>G	p.Phe130Leu	missense_variant	Exon 3 of 5	1	NM_024592.5	ENSP00000264228.4
ENSG00000288695	ENST00000679707.1	c.390C>G	p.Phe130Leu	missense_variant	Exon 3 of 6			ENSP00000505713.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SRD5A3-congenital disorder of glycosylation Uncertain:1

Feb 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with SRD5A3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 130 of the SRD5A3 protein (p.Phe130Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.67
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.75	N
REVEL	Benign	0.077
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.46		Loss of stability (P = 0.1103);
MVP		0.26
MPC		0.28
ClinPred		0.23	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.065
gMVP		0.17

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: rs1719785978; hg19: chr4-56230266;