NM_000413.4:c.539+50C>T

Variant names:

• chr17-42553937-C-T
• rs2676530
• NM_000413.4:c.539+50C>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.539+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,484,782 control chromosomes in the GnomAD database, including 53,044 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 0.24 (4550 hom., cov: 34)
  • Exomes 𝑓: 0.26 (48494 hom.)
• Consequence: HSD17B1 NM_000413.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.51
• Publications: 14 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.276 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B1	NM_000413.4	MANE Select	c.539+50C>T		intron	N/A	NP_000404.2	P14061
	HSD17B1	NM_001330219.3		c.539+50C>T		intron	N/A	NP_001317148.1	A0A0A0MQS7
	HSD17B1-AS1	NR_144402.1		n.866G>A		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B1	ENST00000585807.6	TSL:1 MANE Select	c.539+50C>T		intron	N/A	ENSP00000466799.1	P14061
	HSD17B1	ENST00000225929.5	TSL:2	c.539+50C>T		intron	N/A	ENSP00000225929.5	A0A0A0MQS7
	HSD17B1	ENST00000587280.1	TSL:2	n.922C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35764 AN: 152100 Hom.: 4541 Cov.: 34

Gnomad AFR AF: 0.184

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.0223

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.249 AC: 48921 AN: 196504 AF XY: 0.243

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.337

Gnomad ASJ exome AF: 0.193

Gnomad EAS exome AF: 0.0167

Gnomad FIN exome AF: 0.297

Gnomad NFE exome AF: 0.283

Gnomad OTH exome AF: 0.230

GnomAD4 exome AF: 0.262 AC: 349156 AN: 1332564 Hom.: 48494 Cov.: 20 AF XY: 0.259 AC XY: 172600 AN XY: 665718

African (AFR) AF: 0.175 AC: 5364 AN: 30590

American (AMR) AF: 0.326 AC: 13012 AN: 39876

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 4783 AN: 25064

East Asian (EAS) AF: 0.0113 AC: 420 AN: 37224

South Asian (SAS) AF: 0.184 AC: 14824 AN: 80546

European-Finnish (FIN) AF: 0.295 AC: 14354 AN: 48702

Middle Eastern (MID) AF: 0.151 AC: 839 AN: 5570

European-Non Finnish (NFE) AF: 0.280 AC: 282315 AN: 1009056

Other (OTH) AF: 0.237 AC: 13245 AN: 55936

GnomAD4 genome AF: 0.235 AC: 35777 AN: 152218 Hom.: 4550 Cov.: 34 AF XY: 0.232 AC XY: 17262 AN XY: 74434

African (AFR) AF: 0.183 AC: 7606 AN: 41524

American (AMR) AF: 0.252 AC: 3860 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.192 AC: 667 AN: 3470

East Asian (EAS) AF: 0.0224 AC: 116 AN: 5186

South Asian (SAS) AF: 0.164 AC: 792 AN: 4828

European-Finnish (FIN) AF: 0.295 AC: 3125 AN: 10602

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.279 AC: 18983 AN: 67992

Other (OTH) AF: 0.195 AC: 413 AN: 2114

Alfa AF: 0.170 Hom.: 531

Bravo AF: 0.231

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.54
DANN	Benign	0.78
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs2676530; hg19: chr17-40705955; COSMIC: COSV56798425;