rs605059

Positions:

• chr17-42554888-G-A
• chr17-42554888-G-C
• chr17-42554888-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.52 (20629 hom., cov: 34)
  • Exomes 𝑓: 0.56 (216028 hom.)
• Consequence: HSD17B1 NM_000413.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.73

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

ACMG classification

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/exons	MANE	Protein	UniProt
HSD17B1	NM_000413.4	c.937G>A	p.Gly313Ser	missense_variant	6/6	ENST00000585807.6	NP_000404.2
HSD17B1	NM_001330219.3	c.940G>A	p.Gly314Ser	missense_variant	6/6		NP_001317148.1
HSD17B1	NR_144397.2	n.854G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B1	ENST00000585807.6	c.937G>A	p.Gly313Ser	missense_variant	6/6	1	NM_000413.4	ENSP00000466799	P4
HSD17B1	ENST00000225929.5	c.940G>A	p.Gly314Ser	missense_variant	6/6	2		ENSP00000225929	A2
HSD17B1	ENST00000590299.5	c.*393G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	5		ENSP00000465128
HSD17B1-AS1	ENST00000590513.3			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.519 AC: 78848 AN: 151990 Hom.: 20604 Cov.: 34

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

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.: 56 AF XY: 0.558 AC XY: 382249 AN XY: 685620

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.: 34 AF XY: 0.516 AC XY: 38385 AN XY: 74360

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	T
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	N
LIST_S2	Benign	0.35	T;T
MetaRNN	Benign	0.0000071	T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.64	T
REVEL	Benign	0.0040
Sift4G	Benign	0.56	T;T
Polyphen		0.0020	B;.
Vest4		0.035
MPC		0.30
ClinPred		0.0040	T
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

Other links and lift over

dbSNP: rs605059; hg19: chr17-40706906; COSMIC: COSV56797654; COSMIC: COSV56797654;