17-42554888-G-A

Variant names:

• chr17-42554888-G-A
• rs605059
• NM_000413.4:c.937G>A

Variant summary

Our verdict is Benign. The variant received -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. 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.

• 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
• Publications: 87 publications found

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]

ENSG00000266929 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000413.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B1	NM_000413.4	MANE Select	c.937G>A	p.Gly313Ser	missense	Exon 6 of 6	NP_000404.2
	HSD17B1	NM_001330219.3		c.940G>A	p.Gly314Ser	missense	Exon 6 of 6	NP_001317148.1
	HSD17B1	NR_144397.2		n.854G>A		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B1	ENST00000585807.6	TSL:1 MANE Select	c.937G>A	p.Gly313Ser	missense	Exon 6 of 6	ENSP00000466799.1
	HSD17B1	ENST00000225929.5	TSL:2	c.940G>A	p.Gly314Ser	missense	Exon 6 of 6	ENSP00000225929.5
	HSD17B1	ENST00000590299.5	TSL:5	n.*393G>A		non_coding_transcript_exon	Exon 5 of 5	ENSP00000465128.1

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

GnomAD2 exomes AF: 0.559 AC: 80481 AN: 144020 AF XY: 0.567

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 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

African (AFR) AF: 0.484 AC: 15212 AN: 31408

American (AMR) AF: 0.532 AC: 18158 AN: 34144

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 9540 AN: 24170

East Asian (EAS) AF: 0.454 AC: 16780 AN: 36952

South Asian (SAS) AF: 0.635 AC: 50645 AN: 79786

European-Finnish (FIN) AF: 0.542 AC: 18838 AN: 34728

Middle Eastern (MID) AF: 0.429 AC: 2149 AN: 5010

European-Non Finnish (NFE) AF: 0.562 AC: 608595 AN: 1082788

Other (OTH) AF: 0.532 AC: 30652 AN: 57616

GnomAD4 genome AF: 0.519 AC: 78909 AN: 152108 Hom.: 20629 Cov.: 34 AF XY: 0.516 AC XY: 38385 AN XY: 74360

African (AFR) AF: 0.489 AC: 20301 AN: 41492

American (AMR) AF: 0.483 AC: 7388 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1355 AN: 3470

East Asian (EAS) AF: 0.436 AC: 2248 AN: 5158

South Asian (SAS) AF: 0.637 AC: 3079 AN: 4830

European-Finnish (FIN) AF: 0.529 AC: 5611 AN: 10598

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.549 AC: 37339 AN: 67956

Other (OTH) AF: 0.493 AC: 1043 AN: 2114

Alfa AF: 0.525 Hom.: 17072

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 v4.9

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
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0000071	T
MetaSVM	Benign	-0.89	T
PhyloP100		-3.7
PrimateAI	Uncertain	0.64	T
REVEL	Benign	0.0040
Sift4G	Benign	0.56	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
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

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