dbSNP rs34562248: HSD3B2:p.Ala164Asp (chr1-119421992-C-A) – 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_000198.4(HSD3B2):c.491C>A(p.Ala164Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A164V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HSD3B2
NM_000198.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.363

Publications

0 publications found

Variant links:

Genes affected

HSD3B2 (HGNC:5218): (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2) The protein encoded by this gene is a bifunctional enzyme that catalyzes the oxidative conversion of delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids. It plays a crucial role in the biosynthesis of all classes of hormonal steroids. This gene is predominantly expressed in the adrenals and the gonads. Mutations in this gene are associated with 3-beta-hydroxysteroid dehydrogenase, type II, deficiency. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Oct 2009]

HSD3B2 Gene-Disease associations (from GenCC):

congenital adrenal hyperplasia due to 3-beta-hydroxysteroid dehydrogenase deficiency
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

HSD3B2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
HSD3B2	NM_000198.4 link	c.491C>A	p.Ala164Asp	missense_variant	Exon 4 of 4	ENST00000369416.4	NP_000189.1	P26439-1A0A024R0F9
HSD3B2	NM_001166120.2 link	c.491C>A	p.Ala164Asp	missense_variant	Exon 4 of 4		NP_001159592.1	P26439-1A0A024R0F9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSD3B2	ENST00000369416.4 link	c.491C>A	p.Ala164Asp	missense_variant	Exon 4 of 4	1	NM_000198.4	ENSP00000358424.3	P26439-1
HSD3B2	ENST00000543831.5 link	c.491C>A	p.Ala164Asp	missense_variant	Exon 4 of 4	3		ENSP00000445122.1	P26439-1
HSD3B2	ENST00000433745.5 link	c.491C>A	p.Ala164Asp	missense_variant	Exon 4 of 4	3		ENSP00000388292.1	Q5QP01
HSD3B2	ENST00000448448.2 link	n.435C>A		non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111978

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.82

D;D;D

Eigen

Benign

-0.094

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.87

D;T;.

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.66

D;D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

3.6

H;.;H

PhyloP100

0.36

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.9

D;N;D

REVEL

Pathogenic

0.65

Sift

Benign

0.072

T;T;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.91

P;.;P

Vest4

0.53

MutPred

0.70

Gain of ubiquitination at K159 (P = 0.0645);Gain of ubiquitination at K159 (P = 0.0645);Gain of ubiquitination at K159 (P = 0.0645);

MVP

1.0

MPC

1.0

ClinPred

0.90

GERP RS

3.1

Varity_R

0.57

gMVP

0.84

Mutation Taster

=74/26

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over