chr17-42554255-C-A

Variant names:

• chr17-42554255-C-A
• rs676387
• NM_000413.4:c.540-150C>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.540-150C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 1,118,692 control chromosomes in the GnomAD database, including 48,094 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 0.25 (5213 hom., cov: 34)
  • Exomes 𝑓: 0.29 (42881 hom.)
• Consequence: HSD17B1 NM_000413.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23
• Publications: 41 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B1	NM_000413.4	c.540-150C>A		intron_variant	Intron 4 of 5	ENST00000585807.6	NP_000404.2
HSD17B1-AS1	NR_144402.1	n.548G>T		non_coding_transcript_exon_variant	Exon 1 of 1
HSD17B1	NM_001330219.3	c.540-147C>A		intron_variant	Intron 4 of 5		NP_001317148.1
HSD17B1	NR_144397.2	n.457-150C>A		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B1	ENST00000585807.6	c.540-150C>A		intron_variant	Intron 4 of 5	1	NM_000413.4	ENSP00000466799.1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38501 AN: 152088 Hom.: 5205 Cov.: 34

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.264

GnomAD4 exome AF: 0.290 AC: 280411 AN: 966486 Hom.: 42881 Cov.: 13 AF XY: 0.294 AC XY: 140834 AN XY: 478288

African (AFR) AF: 0.203 AC: 4507 AN: 22236

American (AMR) AF: 0.207 AC: 4199 AN: 20288

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 3360 AN: 17006

East Asian (EAS) AF: 0.444 AC: 14774 AN: 33248

South Asian (SAS) AF: 0.448 AC: 25391 AN: 56684

European-Finnish (FIN) AF: 0.246 AC: 7377 AN: 30024

Middle Eastern (MID) AF: 0.252 AC: 771 AN: 3062

European-Non Finnish (NFE) AF: 0.281 AC: 207890 AN: 741006

Other (OTH) AF: 0.283 AC: 12142 AN: 42932

GnomAD4 genome AF: 0.253 AC: 38528 AN: 152206 Hom.: 5213 Cov.: 34 AF XY: 0.255 AC XY: 18984 AN XY: 74424

African (AFR) AF: 0.201 AC: 8357 AN: 41524

American (AMR) AF: 0.219 AC: 3355 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 687 AN: 3472

East Asian (EAS) AF: 0.416 AC: 2147 AN: 5162

South Asian (SAS) AF: 0.473 AC: 2285 AN: 4828

European-Finnish (FIN) AF: 0.234 AC: 2482 AN: 10596

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18313 AN: 68008

Other (OTH) AF: 0.271 AC: 574 AN: 2116

Alfa AF: 0.247 Hom.: 1598

Bravo AF: 0.245

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.9
DANN	Benign	0.63
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs676387; hg19: chr17-40706273;