Genetic Variant HSD17B2:p.Gly112Arg (chr16-82068238-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002153.3(HSD17B2):c.334G>A(p.Gly112Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

HSD17B2
NM_002153.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.68

Variant links:

Genes affected

HSD17B2 (HGNC:5211): (hydroxysteroid 17-beta dehydrogenase 2) Enables estradiol 17-beta-dehydrogenase activity and testosterone dehydrogenase (NAD+) activity. Involved in response to retinoic acid. Predicted to be located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

HSD17B2 links:

HSD17B2-AS1 (HGNC:56281): (HSD17B2 antisense RNA 1)

HSD17B2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B2	NM_002153.3 link	c.334G>A	p.Gly112Arg	missense_variant	Exon 2 of 5	ENST00000199936.9	NP_002144.1	P37059
HSD17B2	XM_047434049.1 link	c.334G>A	p.Gly112Arg	missense_variant	Exon 2 of 4		XP_047290005.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B2	ENST00000199936.9 link	c.334G>A	p.Gly112Arg	missense_variant	Exon 2 of 5	1	NM_002153.3	ENSP00000199936.4		P37059

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251458

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.334G>A (p.G112R) alteration is located in exon 2 (coding exon 2) of the HSD17B2 gene. This alteration results from a G to A substitution at nucleotide position 334, causing the glycine (G) at amino acid position 112 to be replaced by an arginine (R). 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

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.85

D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.0

M;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.3

D;D

REVEL

Uncertain

0.59

Sift

Uncertain

0.012

D;D

Sift4G

Uncertain

0.010

D;D

Polyphen

1.0

D;.

Vest4

0.87

MutPred

0.71

Loss of catalytic residue at V113 (P = 0.0553);.;

MVP

0.94

MPC

0.021

ClinPred

0.78

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.80

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