dbSNP rs605059: HSD17B1:p.Gly313Ser (chr17-42554888-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000413.4(HSD17B1):c.937G>A(p.Gly313Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.552 in 1,538,710 control chromosomes in the GnomAD database, including 236,657 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.52 ( 20629 hom., cov: 34)

Exomes 𝑓: 0.56 ( 216028 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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.0775586E-6).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B1	NM_000413.4 link	c.937G>A	p.Gly313Ser	missense_variant	Exon 6 of 6	ENST00000585807.6	NP_000404.2	P14061
HSD17B1	NM_001330219.3 link	c.940G>A	p.Gly314Ser	missense_variant	Exon 6 of 6		NP_001317148.1	A0A0A0MQS7
HSD17B1	NR_144397.2 link	n.854G>A		non_coding_transcript_exon_variant	Exon 5 of 5
HSD17B1-AS1	NR_144402.1 link	n.-86C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B1	ENST00000585807.6 link	c.937G>A	p.Gly313Ser	missense_variant	Exon 6 of 6	1	NM_000413.4	ENSP00000466799.1		P14061

Frequencies

GnomAD3 genomes

AF:

0.519

AC:

78848

AN:

151990

Hom.:

20604

Cov.:

show subpopulations

Gnomad AFR

AF:

0.490

Gnomad AMI

AF:

0.465

Gnomad AMR

AF:

0.482

Gnomad ASJ

AF:

0.390

Gnomad EAS

AF:

0.436

Gnomad SAS

AF:

0.639

Gnomad FIN

AF:

0.529

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.549

Gnomad OTH

AF:

0.489

GnomAD3 exomes

AF:

0.559

AC:

80481

AN:

144020

Hom.:

22556

AF XY:

0.567

AC XY:

45575

AN XY:

80412

show subpopulations

Gnomad AFR exome

AF:

0.510

Gnomad AMR exome

AF:

0.542

Gnomad ASJ exome

AF:

0.419

Gnomad EAS exome

AF:

0.456

Gnomad SAS exome

AF:

0.650

Gnomad FIN exome

AF:

0.554

Gnomad NFE exome

AF:

0.575

Gnomad OTH exome

AF:

0.513

GnomAD4 exome

AF:

0.556

AC:

770569

AN:

1386602

Hom.:

216028

Cov.:

AF XY:

0.558

AC XY:

382249

AN XY:

685620

show subpopulations

Gnomad4 AFR exome

AF:

0.484

Gnomad4 AMR exome

AF:

0.532

Gnomad4 ASJ exome

AF:

0.395

Gnomad4 EAS exome

AF:

0.454

Gnomad4 SAS exome

AF:

0.635

Gnomad4 FIN exome

AF:

0.542

Gnomad4 NFE exome

AF:

0.562

Gnomad4 OTH exome

AF:

0.532

GnomAD4 genome

AF:

0.519

AC:

78909

AN:

152108

Hom.:

20629

Cov.:

AF XY:

0.516

AC XY:

38385

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.489

Gnomad4 AMR

AF:

0.483

Gnomad4 ASJ

AF:

0.390

Gnomad4 EAS

AF:

0.436

Gnomad4 SAS

AF:

0.637

Gnomad4 FIN

AF:

0.529

Gnomad4 NFE

AF:

0.549

Gnomad4 OTH

AF:

0.493

Alfa

AF:

0.509

Hom.:

9093

Bravo

AF:

0.510

TwinsUK

AF:

0.564

AC:

2090

ALSPAC

AF:

0.568

AC:

2188

ESP6500AA

AF:

0.573

AC:

2209

ESP6500EA

AF:

0.603

AC:

4593

ExAC

AF:

0.509

AC:

53660

Asia WGS

AF:

0.576

AC:

2004

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Benign

1.6

DANN

Benign

0.65

DEOGEN2

Benign

0.13

T;T

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0073

LIST_S2

Benign

0.35

T;T

MetaRNN

Benign

0.0000071

T;T

MetaSVM

Benign

-0.89

PrimateAI

Uncertain

0.64

REVEL

Benign

0.0040

Sift4G

Benign

0.56

T;T

Polyphen

0.0020

B;.

Vest4

0.035

MPC

0.30

ClinPred

0.0040

GERP RS

-1.2

Varity_R

0.041

gMVP

0.10

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