5-6656129-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001047.4(SRD5A1):c.512T>C(p.Ile171Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SRD5A1 NM_001047.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.72

Genes affected

SRD5A1 (HGNC:11284): (steroid 5 alpha-reductase 1) Steroid 5-alpha-reductase (EC 1.3.99.5) catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone (DHT). Also see SRD5A2 (MIM 607306).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A1	NM_001047.4	c.512T>C	p.Ile171Thr	missense_variant	3/5	ENST00000274192.7
SRD5A1	NM_001324322.2	c.371T>C	p.Ile124Thr	missense_variant	2/4
SRD5A1	NM_001324323.2	c.293T>C	p.Ile98Thr	missense_variant	4/6
SRD5A1	NR_136739.2	n.839T>C		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A1	ENST00000274192.7	c.512T>C	p.Ile171Thr	missense_variant	3/5	1	NM_001047.4	P1
SRD5A1	ENST00000504286.2	c.702T>C	p.Tyr234=	synonymous_variant, NMD_transcript_variant	4/6	2
SRD5A1	ENST00000513117.1	c.345T>C	p.Tyr115=	synonymous_variant, NMD_transcript_variant	2/4	2
SRD5A1	ENST00000510531.6	c.*633T>C		3_prime_UTR_variant, NMD_transcript_variant	4/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251348 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461766 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2022

The c.512T>C (p.I171T) alteration is located in exon 3 (coding exon 3) of the SRD5A1 gene. This alteration results from a T to C substitution at nucleotide position 512, causing the isoleucine (I) at amino acid position 171 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.28
Sift	Benign	0.050	D
Sift4G	Benign	0.083	T
Polyphen		0.62	P
Vest4		0.69
MutPred		0.79		Loss of stability (P = 0.0086);
MVP		0.63
MPC		1.3
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.36
gMVP		0.73

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: rs745463060; hg19: chr5-6656242;