4-55346358-G-T

Variant names:

• chr4-55346358-G-T
• rs539407364
• NM_024592.5:c.22G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_024592.5(SRD5A3):​c.22G>T​(p.Glu8*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,377,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SRD5A3 NM_024592.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P

ENSG00000288695 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.22G>T	p.Glu8*	stop_gained	Exon 1 of 5	NP_078868.1	Q9H8P0
	SRD5A3	NM_001410732.1		c.22G>T	p.Glu8*	stop_gained	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.22G>T	p.Glu8*	stop_gained	Exon 1 of 5	ENSP00000264228.4	Q9H8P0
	ENSG00000288695	ENST00000679707.1		c.22G>T	p.Glu8*	stop_gained	Exon 1 of 6	ENSP00000505713.1	A0A7P0T9P9
	SRD5A3	ENST00000918496.1		c.22G>T	p.Glu8*	stop_gained	Exon 1 of 5	ENSP00000588555.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1377050 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 680454

⚠️ 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: 28300

American (AMR) AF: 0.0000300 AC: 1 AN: 33304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24118

East Asian (EAS) AF: 0.00 AC: 0 AN: 31708

South Asian (SAS) AF: 0.00 AC: 0 AN: 77392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5026

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072512

Other (OTH) AF: 0.00 AC: 0 AN: 56934

⚠️ 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 Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.0049
FATHMM_MKL	Benign	0.059	N
PhyloP100		1.1
Vest4		0.046
GERP RS		3.8
PromoterAI		0.27	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=31/169	disease causing (fs/PTC)

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: rs539407364; hg19: chr4-56212525;