rs597255

Variant names:

• chr17-42553082-C-T
• rs597255
• NM_000413.4:c.98-42C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000413.4(HSD17B1):​c.98-42C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 1,613,528 control chromosomes in the GnomAD database, including 254,706 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.56 (24483 hom., cov: 33)
  • Exomes 𝑓: 0.56 (230223 hom.)
• Consequence: HSD17B1 NM_000413.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520
• Publications: 21 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]

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

ENSG00000266929 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.64 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B1	NM_000413.4	c.98-42C>T		intron_variant	Intron 1 of 5	ENST00000585807.6	NP_000404.2
HSD17B1-AS1	NR_144402.1	n.1721G>A		non_coding_transcript_exon_variant	Exon 1 of 1
HSD17B1	NM_001330219.3	c.98-42C>T		intron_variant	Intron 1 of 5		NP_001317148.1
HSD17B1	NR_144397.2	n.109-42C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B1	ENST00000585807.6	c.98-42C>T		intron_variant	Intron 1 of 5	1	NM_000413.4	ENSP00000466799.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85715 AN: 151938 Hom.: 24461 Cov.: 33

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.391

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.642

Gnomad FIN AF: 0.531

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.511

GnomAD2 exomes AF: 0.548 AC: 137557 AN: 250924 AF XY: 0.550

Gnomad AFR exome AF: 0.648

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.394

Gnomad EAS exome AF: 0.437

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.551

Gnomad OTH exome AF: 0.508

GnomAD4 exome AF: 0.559 AC: 816305 AN: 1461472 Hom.: 230223 Cov.: 56 AF XY: 0.559 AC XY: 406676 AN XY: 727026

African (AFR) AF: 0.644 AC: 21547 AN: 33472

American (AMR) AF: 0.535 AC: 23944 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 10235 AN: 26126

East Asian (EAS) AF: 0.452 AC: 17934 AN: 39690

South Asian (SAS) AF: 0.633 AC: 54585 AN: 86252

European-Finnish (FIN) AF: 0.540 AC: 28740 AN: 53248

Middle Eastern (MID) AF: 0.433 AC: 2495 AN: 5760

European-Non Finnish (NFE) AF: 0.561 AC: 624101 AN: 1111824

Other (OTH) AF: 0.542 AC: 32724 AN: 60384

GnomAD4 genome AF: 0.564 AC: 85778 AN: 152056 Hom.: 24483 Cov.: 33 AF XY: 0.560 AC XY: 41631 AN XY: 74316

African (AFR) AF: 0.646 AC: 26817 AN: 41484

American (AMR) AF: 0.498 AC: 7612 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 1356 AN: 3470

East Asian (EAS) AF: 0.439 AC: 2256 AN: 5144

South Asian (SAS) AF: 0.640 AC: 3090 AN: 4826

European-Finnish (FIN) AF: 0.531 AC: 5615 AN: 10578

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.550 AC: 37393 AN: 67958

Other (OTH) AF: 0.516 AC: 1090 AN: 2114

Alfa AF: 0.560 Hom.: 10694

Bravo AF: 0.562

Asia WGS AF: 0.593 AC: 2062 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.43
DANN	Benign	0.34
PhyloP100		-0.052
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs597255; hg19: chr17-40705100; COSMIC: COSV56797842; COSMIC: COSV56797842;