Genetic Variant NM_000348.4:c.*1152delT (chr2-31525043-TA-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000348.4(SRD5A2):c.*1152delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 191,082 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.021 ( 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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

46,XY disorder of sex development due to 5-alpha-reductase 2 deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

SRD5A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Variant has high frequency in the AFR (0.0211) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000348.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A2	NM_000348.4	MANE Select	c.*1152delT		3_prime_UTR	Exon 5 of 5	NP_000339.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SRD5A2	ENST00000622030.2	TSL:1 MANE Select	c.*1152delT	3_prime_UTR	Exon 5 of 5	ENSP00000477587.1	P31213
SRD5A2	ENST00000882642.1		c.*1152delT	3_prime_UTR	Exon 6 of 6	ENSP00000552701.1
SRD5A2	ENST00000882643.1		c.*1152delT	3_prime_UTR	Exon 4 of 4	ENSP00000552702.1

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

180

AN:

141304

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000637

Gnomad ASJ

AF:

0.00121

Gnomad EAS

AF:

0.00101

Gnomad SAS

AF:

0.000898

Gnomad FIN

AF:

0.000818

Gnomad MID

AF:

0.00336

Gnomad NFE

AF:

0.000576

Gnomad OTH

AF:

0.00263

GnomAD4 exome

AF:

0.0211

AC:

1048

AN:

49730

Hom.:

Cov.:

AF XY:

0.0200

AC XY:

461

AN XY:

23060

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0265

AC:

AN:

2186

American (AMR)

AF:

0.0246

AC:

AN:

1422

Ashkenazi Jewish (ASJ)

AF:

0.0211

AC:

AN:

3176

East Asian (EAS)

AF:

0.0163

AC:

126

AN:

7732

South Asian (SAS)

AF:

0.0220

AC:

AN:

410

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.0185

AC:

AN:

324

European-Non Finnish (NFE)

AF:

0.0222

AC:

673

AN:

30280

Other (OTH)

AF:

0.0178

AC:

AN:

4160

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

184

277

369

461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00129

AC:

182

AN:

141352

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

68518

show subpopulations

African (AFR)

AF:

0.00282

AC:

109

AN:

38624

American (AMR)

AF:

0.000636

AC:

AN:

14150

Ashkenazi Jewish (ASJ)

AF:

0.00121

AC:

AN:

3306

East Asian (EAS)

AF:

0.00101

AC:

AN:

4934

South Asian (SAS)

AF:

0.000901

AC:

AN:

4438

European-Finnish (FIN)

AF:

0.000818

AC:

AN:

8558

Middle Eastern (MID)

AF:

0.00368

AC:

AN:

272

European-Non Finnish (NFE)

AF:

0.000576

AC:

AN:

64260

Other (OTH)

AF:

0.00313

AC:

AN:

1918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000110

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

3-Oxo-5 alpha-steroid delta 4-dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.41

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over