Variant 12-56784855-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003725.4(HSD17B6):c.575G>A(p.Arg192His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,612,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

HSD17B6
NM_003725.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.11

Variant links:

Genes affected

HSD17B6 (HGNC:23316): (hydroxysteroid 17-beta dehydrogenase 6) The protein encoded by this gene has both oxidoreductase and epimerase activities and is involved in androgen catabolism. The oxidoreductase activity can convert 3 alpha-adiol to dihydrotestosterone, while the epimerase activity can convert androsterone to epi-androsterone. Both reactions use NAD+ as the preferred cofactor. This gene is a member of the retinol dehydrogenase family. [provided by RefSeq, Aug 2013]

HSD17B6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25886363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B6	NM_003725.4 linkuse as main transcript	c.575G>A	p.Arg192His	missense_variant, splice_region_variant	4/5	ENST00000322165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B6	ENST00000322165.1 linkuse as main transcript	c.575G>A	p.Arg192His	missense_variant, splice_region_variant	4/5	1	NM_003725.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

250084

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135160

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000879

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000335

AC:

AN:

1460616

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

726550

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000158

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000140

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000131

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000957

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.000208

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

The c.575G>A (p.R192H) alteration is located in exon 4 (coding exon 3) of the HSD17B6 gene. This alteration results from a G to A substitution at nucleotide position 575, causing the arginine (R) at amino acid position 192 to be replaced by a histidine (H). 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

Uncertain

0.39

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;D;D;D;D

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.86

.;.;.;.;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.28

N;N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.9

D;D;D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.020

D;D;D;D;D

Sift4G

Uncertain

0.033

D;D;D;D;D

Polyphen

0.40

B;B;B;B;B

Vest4

0.33

MVP

0.82

MPC

0.26

ClinPred

0.14

GERP RS

1.6

Varity_R

0.17

gMVP

0.36

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