4-55364217-T-C

Variant summary

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

The NM_024592.5(SRD5A3):ā€‹c.508T>Cā€‹(p.Tyr170His) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.000017 ( 0 hom. )

Consequence

SRD5A3
NM_024592.5 missense

Scores

3
11
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.06
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 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 rank MANE Protein UniProt
SRD5A3NM_024592.5 linkc.508T>C p.Tyr170His missense_variant Exon 3 of 5 ENST00000264228.9 NP_078868.1 Q9H8P0
SRD5A3NM_001410732.1 linkc.508T>C p.Tyr170His missense_variant Exon 3 of 4 NP_001397661.1
SRD5A3XM_017008601.2 linkc.373T>C p.Tyr125His missense_variant Exon 3 of 5 XP_016864090.1
SRD5A3XM_005265767.4 linkc.364+4729T>C 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.508T>C p.Tyr170His missense_variant Exon 3 of 5 1 NM_024592.5 ENSP00000264228.4 Q9H8P0
ENSG00000288695ENST00000679707.1 linkc.508T>C p.Tyr170His missense_variant Exon 3 of 6 ENSP00000505713.1 A0A7P0T9P9

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152170
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:
0.000771
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000597
AC:
15
AN:
251462
Hom.:
0
AF XY:
0.0000589
AC XY:
8
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:
0.000815
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:
0.0000171
AC:
25
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.0000179
AC XY:
13
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000202
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000771
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.0000659
AC:
8

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Mar 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.508T>C (p.Y170H) alteration is located in exon 3 (coding exon 3) of the SRD5A3 gene. This alteration results from a T to C substitution at nucleotide position 508, causing the tyrosine (Y) at amino acid position 170 to be replaced by a histidine (H). 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
0.42
BayesDel_addAF
Uncertain
0.068
T
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.82
T
M_CAP
Benign
0.057
D
MetaRNN
Uncertain
0.67
D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Pathogenic
3.5
M
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-4.4
D
REVEL
Uncertain
0.49
Sift
Benign
0.047
D
Sift4G
Benign
0.075
T
Polyphen
0.98
D
Vest4
0.91
MutPred
0.47
Gain of catalytic residue at L172 (P = 0.0566);
MVP
0.87
MPC
0.87
ClinPred
0.91
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.45
gMVP
0.85

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: rs778788864; hg19: chr4-56230384; API