rs767564684

Variant summary

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

The NM_000348.4(SRD5A2):​c.620C>T​(p.Ala207Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SRD5A2
NM_000348.4 missense

Scores

5
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.00
Variant links:
Genes affected
SRD5A2 (HGNC:11285): (steroid 5 alpha-reductase 2) This gene encodes a microsomal protein expressed at high levels in androgen-sensitive tissues such as the prostate. The encoded protein is active at acidic pH and is sensitive to the 4-azasteroid inhibitor finasteride. Deficiencies in this gene can result in male pseudohermaphroditism, specifically pseudovaginal perineoscrotal hypospadias (PPSH). [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SRD5A2NM_000348.4 linkuse as main transcriptc.620C>T p.Ala207Val missense_variant 4/5 ENST00000622030.2 NP_000339.2 P31213
SRD5A2XM_011533069.3 linkuse as main transcriptc.398C>T p.Ala133Val missense_variant 4/5 XP_011531371.1
SRD5A2XM_011533072.3 linkuse as main transcriptc.365C>T p.Ala122Val missense_variant 6/7 XP_011531374.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SRD5A2ENST00000622030.2 linkuse as main transcriptc.620C>T p.Ala207Val missense_variant 4/51 NM_000348.4 ENSP00000477587.1 P31213
ENSG00000228563ENST00000435713.1 linkuse as main transcriptn.255+1685G>A intron_variant 3

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
LINK: link

Submissions by phenotype

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGMJun 22, 2023The observed missense variant c.620C>T(p.Thr207Ile) in SRD5A2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.620C>T(p.Thr207Ile) variant is reported with 0.0004% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Pathogenic/Likely Pathogenic. However, no details are available for independent assessment. The variant is predicted to be damaging by SIFT. The amino acid Thr at position 207 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Thr207Ile in SRD5A2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Uncertain
0.073
D
BayesDel_noAF
Benign
-0.13
CADD
Uncertain
25
DANN
Benign
0.73
FATHMM_MKL
Uncertain
0.92
D
MetaRNN
Uncertain
0.60
D
PrimateAI
Uncertain
0.60
T
Sift4G
Benign
0.063
T
Vest4
0.55
MVP
0.56
GERP RS
5.7
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-31754455; API