Genetic Variant SRD5A2:c.*1151_*1152dupTT (chr2-31525043-T-TAA) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_000348.4(SRD5A2):c.*1151_*1152dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 190,274 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 32)

Exomes 𝑓: 0.014 ( 0 hom. )

Consequence

SRD5A2
NM_000348.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.414

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]

SRD5A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0016 (226/141308) while in subpopulation SAS AF = 0.0435 (193/4438). AF 95% confidence interval is 0.0385. There are 2 homozygotes in GnomAd4. There are 163 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SRD5A2	NM_000348.4 link	c.1151_1152dupTT	3_prime_UTR_variant	Exon 5 of 5	ENST00000622030.2	NP_000339.2	P31213
SRD5A2	XM_011533069.3 link	c.1151_1152dupTT	3_prime_UTR_variant	Exon 5 of 5		XP_011531371.1
SRD5A2	XM_011533072.3 link	c.1151_1152dupTT	3_prime_UTR_variant	Exon 7 of 7		XP_011531374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A2	ENST00000622030 link	c.1151_1152dupTT		3_prime_UTR_variant	Exon 5 of 5	1	NM_000348.4	ENSP00000477587.1		P31213

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

229

AN:

141262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000467

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000142

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000606

Gnomad SAS

AF:

0.0440

Gnomad FIN

AF:

0.000234

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000934

Gnomad OTH

AF:

0.00105

GnomAD4 exome

AF:

0.0140

AC:

684

AN:

48966

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

299

AN XY:

22714

show subpopulations

Gnomad4 AFR exome

AF:

0.0157

AC:

AN:

2168

Gnomad4 AMR exome

AF:

0.0213

AC:

AN:

1410

Gnomad4 ASJ exome

AF:

0.0115

AC:

AN:

3134

Gnomad4 EAS exome

AF:

0.0111

AC:

AN:

7636

Gnomad4 SAS exome

AF:

0.0470

AC:

AN:

404

Gnomad4 FIN exome

AF:

0.0250

AC:

AN:

Gnomad4 NFE exome

AF:

0.0138

AC:

413

AN:

29822

Gnomad4 Remaining exome

AF:

0.0158

AC:

AN:

4042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

136

203

271

339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00160

AC:

226

AN:

141308

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

163

AN XY:

68484

show subpopulations

Gnomad4 AFR

AF:

0.000466

AC:

0.000466007

AN:

0.000466007

Gnomad4 AMR

AF:

0.000142

AC:

0.000141503

AN:

0.000141503

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000608

AC:

0.00060778

AN:

0.00060778

Gnomad4 SAS

AF:

0.0435

AC:

0.0434881

AN:

0.0434881

Gnomad4 FIN

AF:

0.000234

AC:

0.000233973

AN:

0.000233973

Gnomad4 NFE

AF:

0.0000934

AC:

0.0000933998

AN:

0.0000933998

Gnomad4 OTH

AF:

0.00104

AC:

0.00104384

AN:

0.00104384

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over