chr4-55364125-A-G

Position:

• chr4-55364125-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024592.5(SRD5A3):​c.416A>G​(p.His139Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 7.27

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRD5A3	NM_024592.5	c.416A>G	p.His139Arg	missense_variant	3/5	ENST00000264228.9	NP_078868.1
SRD5A3	NM_001410732.1	c.416A>G	p.His139Arg	missense_variant	3/4		NP_001397661.1
SRD5A3	XM_017008601.2	c.281A>G	p.His94Arg	missense_variant	3/5		XP_016864090.1
SRD5A3	XM_005265767.4	c.364+4637A>G		intron_variant			XP_005265824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRD5A3	ENST00000264228.9	c.416A>G	p.His139Arg	missense_variant	3/5	1	NM_024592.5	ENSP00000264228.4
ENSG00000288695	ENST00000679707.1	c.416A>G	p.His139Arg	missense_variant	3/6			ENSP00000505713.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SRD5A3-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 19, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.018	D
Polyphen		0.34	B
Vest4		0.91
MutPred		0.73		Gain of MoRF binding (P = 0.0099);
MVP		0.74
MPC		0.95
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.41
gMVP		0.89

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: rs1719786702; hg19: chr4-56230292;