NM_024592.5:c.506A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_024592.5(SRD5A3):​c.506A>G​(p.Tyr169Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,976 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000075 ( 0 hom. )

Consequence

SRD5A3
NM_024592.5 missense

Scores

8
9
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 9.05
Variant links:
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-AS1 (HGNC:44138): (SRD5A3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963
PP5
Variant 4-55364215-A-G is Pathogenic according to our data. Variant chr4-55364215-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2506565.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SRD5A3NM_024592.5 linkc.506A>G p.Tyr169Cys missense_variant Exon 3 of 5 ENST00000264228.9 NP_078868.1 Q9H8P0
SRD5A3NM_001410732.1 linkc.506A>G p.Tyr169Cys missense_variant Exon 3 of 4 NP_001397661.1
SRD5A3XM_017008601.2 linkc.371A>G p.Tyr124Cys missense_variant Exon 3 of 5 XP_016864090.1
SRD5A3XM_005265767.4 linkc.364+4727A>G intron_variant Intron 2 of 2 XP_005265824.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SRD5A3ENST00000264228.9 linkc.506A>G p.Tyr169Cys missense_variant Exon 3 of 5 1 NM_024592.5 ENSP00000264228.4 Q9H8P0
ENSG00000288695ENST00000679707.1 linkc.506A>G p.Tyr169Cys missense_variant Exon 3 of 6 ENSP00000505713.1 A0A7P0T9P9

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152088
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251460
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.00000963
AC XY:
7
AN XY:
727244
show subpopulations
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:
0.0000927
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152088
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

SRD5A3-congenital disorder of glycosylation Pathogenic:1Uncertain:1
Jun 24, 2023
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This novel homozygous variant has been identified in a proband with global developmental delay, deep set eyes, nystagmus, bilateral epicanthal folds, temporal balding, flapping of hands, happy demeanor, self absorbed. This variant has been identified in 0.0028% in gnomAD (aggregated) (PM2_moderate). -

Dec 06, 2024
Molecular Genetics, Royal Melbourne Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change in SRD5A3 is predicted to replace tyrosine with cysteine at codon 169, p.(Tyr169Cys). The tyrosine residue is highly conserved (100 vertebrates, Multiz Alignments), and is located in the 3-oxo-5-alpha-steroid 4-dehydrogenase C-terminal domain. There is a large physicochemical difference between tyrosine and cysteine. The highest population minor allele frequency in the population database gnomAD v4.1 is 0.009% (8/91,080 alleles) in the South Asian population, consistent with recessive disease. This variant has been detected as homozygous in at least four individuals with a phenotype consistent with SRD5A3-congenital disorder of glycosylation and segregates with disease in two families (PMID: 21937992; doi: https://doi.org/10.1101/2024.01.08.23299914; ClinVar: SCV003935142.1; this individual). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.664) and predicts no impact on splicing (SpliceAI) for the nucleotide change. Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2_Supporting, PM3, PP1_Strong, PP3. -

Kahrizi syndrome Pathogenic:1
Feb 16, 2025
Palindrome, Gene Kavoshgaran Aria
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Sep 07, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21937992) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.25
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.72
D
Eigen
Pathogenic
0.73
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D
M_CAP
Uncertain
0.097
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Pathogenic
3.1
M
PrimateAI
Uncertain
0.62
T
PROVEAN
Pathogenic
-6.6
D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.97
MVP
0.88
MPC
0.99
ClinPred
0.94
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.66
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754837473; hg19: chr4-56230382; API