Genetic Variant HSD17B1:p.Gly313Arg (chr17-42554888-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000413.4(HSD17B1):c.937G>C(p.Gly313Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000916 in 1,539,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 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. G313S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

HSD17B1
NM_000413.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.73

Variant links:

Genes affected

HSD17B1 (HGNC:5210): (hydroxysteroid 17-beta dehydrogenase 1) This gene encodes a member of the 17beta-hydroxysteroid dehydrogenase family of short-chain dehydrogenases/reductases. It has a dual function in estrogen activation and androgen inactivation and plays a major role in establishing the estrogen E2 concentration gradient between serum and peripheral tissues. The encoded protein catalyzes the last step in estrogen activation, using NADPH to convert estrogens E1 and E2 and androgens like 4-androstenedione, to testosterone. It has an N-terminal short-chain dehydrogenase domain with a cofactor binding site, and a narrow, hydrophobic C-terminal domain with a steroid substrate binding site. This gene is expressed primarily in the placenta and ovarian granulosa cells, and to a lesser extent, in the endometrium, adipose tissue, and prostate. Polymorphisms in this gene have been linked to breast and prostate cancer. A pseudogene of this gene has been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

HSD17B1 links:

ENSG00000266929 (HGNC:):

ENSG00000266929 links:

HSD17B1-AS1 (HGNC:55314): (HSD17B1 antisense RNA 1)

HSD17B1-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019367307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B1	NM_000413.4 link	c.937G>C	p.Gly313Arg	missense_variant	Exon 6 of 6	ENST00000585807.6	NP_000404.2	P14061
HSD17B1	NM_001330219.3 link	c.940G>C	p.Gly314Arg	missense_variant	Exon 6 of 6		NP_001317148.1	A0A0A0MQS7
HSD17B1	NR_144397.2 link	n.854G>C		non_coding_transcript_exon_variant	Exon 5 of 5
HSD17B1-AS1	NR_144402.1 link	n.-86C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B1	ENST00000585807.6 link	c.937G>C	p.Gly313Arg	missense_variant	Exon 6 of 6	1	NM_000413.4	ENSP00000466799.1		P14061

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000177

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000903

AC:

AN:

144020

Hom.:

AF XY:

0.0000995

AC XY:

AN XY:

80412

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:

0.00

Gnomad FIN exome

AF:

0.000593

Gnomad NFE exome

AF:

0.000148

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000887

AC:

123

AN:

1386848

Hom.:

Cov.:

AF XY:

0.0000729

AC XY:

AN XY:

685756

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000271

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.000835

Gnomad4 NFE exome

AF:

0.0000776

Gnomad4 OTH exome

AF:

0.000139

GnomAD4 genome

AF:

0.000118

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.000177

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000123

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.25

CADD

Benign

1.7

DANN

Benign

0.66

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.39

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.019

T;T

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.67

REVEL

Benign

0.014

Sift4G

Benign

0.10

T;T

Polyphen

0.50

P;.

Vest4

0.094

MVP

0.42

MPC

0.35

ClinPred

0.054

GERP RS

-1.2

Varity_R

0.073

gMVP

0.096

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over