5-6633640-G-A

Position:

• chr5-6633640-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001047.4(SRD5A1):​c.64G>A​(p.Ala22Thr) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SRD5A1 NM_001047.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.878

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07187024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRD5A1	NM_001047.4	c.64G>A	p.Ala22Thr	missense_variant	1/5	ENST00000274192.7
SRD5A1	NM_001324322.2	c.90G>A	p.Ala30=	synonymous_variant	1/4
SRD5A1	NM_001324323.2	c.-658G>A		5_prime_UTR_variant	1/6
SRD5A1	NR_136739.2	n.201G>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRD5A1	ENST00000274192.7	c.64G>A	p.Ala22Thr	missense_variant	1/5	1	NM_001047.4	P1
SRD5A1	ENST00000504286.2	c.64G>A	p.Ala22Thr	missense_variant, NMD_transcript_variant	1/6	2
SRD5A1	ENST00000513117.1	c.64G>A	p.Ala22Thr	missense_variant, NMD_transcript_variant	1/4	2
SRD5A1	ENST00000510531.6	c.64G>A	p.Ala22Thr	missense_variant, NMD_transcript_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1403730 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 695166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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

Jul 25, 2023

The c.64G>A (p.A22T) alteration is located in exon 1 (coding exon 1) of the SRD5A1 gene. This alteration results from a G to A substitution at nucleotide position 64, causing the alanine (A) at amino acid position 22 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	Benign	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.3
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.014
Sift	Benign	0.33	T
Sift4G	Benign	0.48	T
Polyphen		0.35	B
Vest4		0.22
MutPred		0.40		Loss of MoRF binding (P = 0.1534);
MVP		0.11
MPC		0.50
ClinPred		0.27	T
GERP RS		-1.4
Varity_R		0.040
gMVP		0.38

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: rs1195088921; hg19: chr5-6633753;