Genetic Variant NM_024592.5:c.-40G>A (chr4-55346297-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024592.5(SRD5A3):c.-40G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,368,586 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 45 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 36 hom. )

Consequence

SRD5A3
NM_024592.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.143

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

SRD5A3-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P

SRD5A3 links:

ENSG00000288695 (HGNC:):

ENSG00000288695 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 4-55346297-G-A is Benign according to our data. Variant chr4-55346297-G-A is described in ClinVar as Benign. ClinVar VariationId is 349004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.05 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024592.5. 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
	SRD5A3	NM_024592.5	MANE Select	c.-40G>A		5_prime_UTR	Exon 1 of 5	NP_078868.1	Q9H8P0
	SRD5A3	NM_001410732.1		c.-40G>A		5_prime_UTR	Exon 1 of 4	NP_001397661.1	A0A7P0TBH6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SRD5A3	ENST00000264228.9	TSL:1 MANE Select	c.-40G>A	5_prime_UTR	Exon 1 of 5	ENSP00000264228.4	Q9H8P0
ENSG00000288695	ENST00000679707.1		c.-40G>A	5_prime_UTR	Exon 1 of 6	ENSP00000505713.1	A0A7P0T9P9
SRD5A3	ENST00000918496.1		c.-40G>A	5_prime_UTR	Exon 1 of 5	ENSP00000588555.1

Frequencies

GnomAD3 genomes

AF:

0.0135

AC:

2060

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0475

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00272

AC:

AN:

11022

AF XY:

0.00142

show subpopulations

Gnomad AFR exome

AF:

0.0779

Gnomad AMR exome

AF:

0.00517

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00121

AC:

1473

AN:

1216346

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

616

AN XY:

592004

show subpopulations

African (AFR)

AF:

0.0525

AC:

1255

AN:

23924

American (AMR)

AF:

0.00387

AC:

AN:

10330

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16616

East Asian (EAS)

AF:

0.00

AC:

AN:

27378

South Asian (SAS)

AF:

0.0000579

AC:

AN:

51802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35290

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

3458

European-Non Finnish (NFE)

AF:

0.0000221

AC:

AN:

997702

Other (OTH)

AF:

0.00301

AC:

150

AN:

49846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

143

214

286

357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.0136

AC:

2067

AN:

152240

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

1001

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0476

AC:

1978

AN:

41570

American (AMR)

AF:

0.00458

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67978

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

104

208

311

415

519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0130

Hom.:

Bravo

AF:

0.0150

Asia WGS

AF:

0.00232

AC:

AN:

3468

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

SRD5A3-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.14

PromoterAI

-0.087

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Mutation Taster

=300/0

polymorphism

(source)

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

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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