17-42554661-C-T

Position:

• chr17-42554661-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000413.4(HSD17B1):​c.718-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,604,372 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (11 hom., cov: 34)
  • Exomes 𝑓: 0.012 (174 hom.)
• Consequence: HSD17B1 NM_000413.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004899
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.19

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-42554661-C-T is Benign according to our data. Variant chr17-42554661-C-T is described in ClinVar as [Benign]. Clinvar id is 771028.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B1	NM_000413.4	c.718-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000585807.6
HSD17B1-AS1	NR_144402.1	n.142G>A		non_coding_transcript_exon_variant	1/1
HSD17B1	NM_001330219.3	c.721-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
HSD17B1	NR_144397.2	n.635-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B1	ENST00000585807.6	c.718-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000413.4	P4
HSD17B1-AS1	ENST00000590513.3	n.181G>A		non_coding_transcript_exon_variant	1/1
HSD17B1	ENST00000225929.5	c.721-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		A2
HSD17B1	ENST00000590299.5	c.*174-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00790 AC: 1203 AN: 152242 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00961

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00785 AC: 1844 AN: 235054 Hom.: 15 AF XY: 0.00738 AC XY: 954 AN XY: 129250

Gnomad AFR exome AF: 0.00272

Gnomad AMR exome AF: 0.00639

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000362

Gnomad FIN exome AF: 0.00436

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.0121 AC: 17522 AN: 1452012 Hom.: 174 Cov.: 31 AF XY: 0.0116 AC XY: 8400 AN XY: 722456

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.00666

Gnomad4 ASJ exome AF: 0.00707

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000534

Gnomad4 FIN exome AF: 0.00495

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.00939

GnomAD4 genome AF: 0.00790 AC: 1203 AN: 152360 Hom.: 11 Cov.: 34 AF XY: 0.00707 AC XY: 527 AN XY: 74502

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.00960

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00235

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.0110 Hom.: 4

Bravo AF: 0.00816

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0119

EpiControl AF: 0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 02, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.9
DANN	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000049
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.010		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: rs113690224; hg19: chr17-40706679;