Genetic Variant HSD3B1:p.Val78Phe (chr1-119511589-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_000862.3(HSD3B1):c.232G>T(p.Val78Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,613,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

HSD3B1
NM_000862.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.53

Variant links:

Genes affected

HSD3B1 (HGNC:5217): (hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1) The protein encoded by this gene is an enzyme that catalyzes the oxidative conversion of delta-5-3-beta-hydroxysteroid precursors into delta-4-ketosteroids, which leads to the production of all classes of steroid hormones. The encoded protein also catalyzes the interconversion of 3-beta-hydroxy- and 3-keto-5-alpha-androstane steroids. [provided by RefSeq, Jun 2016]

HSD3B1 links:

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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
HSD3B1	NM_000862.3 link	c.232G>T	p.Val78Phe	missense_variant	Exon 3 of 4	ENST00000369413.8	NP_000853.1	P14060
HSD3B1	NM_001328615.1 link	c.232G>T	p.Val78Phe	missense_variant	Exon 3 of 4		NP_001315544.1	P14060

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSD3B1	ENST00000369413.8 link	c.232G>T	p.Val78Phe	missense_variant	Exon 3 of 4	1	NM_000862.3	ENSP00000358421.3	P14060
HSD3B1	ENST00000528909.1 link	c.232G>T	p.Val78Phe	missense_variant	Exon 2 of 3	1		ENSP00000432268.1	P14060
HSD3B1	ENST00000531340.5 link	c.232G>T	p.Val78Phe	missense_variant	Exon 3 of 3	3		ENSP00000435999.1	E9PRN7
HSD3B1	ENST00000492140.1 link	n.367G>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152110

Hom.:

Cov.:

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:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000112

AC:

AN:

250962

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135620

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000119

AC:

174

AN:

1461482

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000371

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.232G>T (p.V78F) alteration is located in exon 3 (coding exon 2) of the HSD3B1 gene. This alteration results from a G to T substitution at nucleotide position 232, causing the valine (V) at amino acid position 78 to be replaced by a phenylalanine (F). 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

Benign

0.22

BayesDel_addAF

Benign

-0.045

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.61

D;D;D

Eigen

Benign

-0.085

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.81

T;.;D

M_CAP

Benign

0.055

MetaRNN

Uncertain

0.50

D;D;D

MetaSVM

Uncertain

-0.21

MutationAssessor

Pathogenic

3.2

.;M;M

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.2

D;N;N

REVEL

Uncertain

0.58

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.99

.;D;D

Vest4

0.56

MVP

0.94

MPC

0.22

ClinPred

0.58

GERP RS

2.3

Varity_R

0.37

gMVP

0.51

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.

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