17-42554888-G-C

Position:

• chr17-42554888-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000585807.6(HSD17B1):​c.937G>C​(p.Gly313Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000916 in 1,539,010 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G313S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: HSD17B1 ENST00000585807.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.73

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.019367307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD17B1	NM_000413.4	c.937G>C	p.Gly313Arg	missense_variant	6/6	ENST00000585807.6	NP_000404.2
HSD17B1	NM_001330219.3	c.940G>C	p.Gly314Arg	missense_variant	6/6		NP_001317148.1
HSD17B1	NR_144397.2	n.854G>C		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B1	ENST00000585807.6	c.937G>C	p.Gly313Arg	missense_variant	6/6	1	NM_000413.4	ENSP00000466799	P4
HSD17B1	ENST00000225929.5	c.940G>C	p.Gly314Arg	missense_variant	6/6	2		ENSP00000225929	A2
HSD17B1	ENST00000590299.5	c.*393G>C		3_prime_UTR_variant, NMD_transcript_variant	5/5	5		ENSP00000465128
HSD17B1-AS1	ENST00000590513.3			upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152044 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000903 AC: 13 AN: 144020 Hom.: 0 AF XY: 0.0000995 AC XY: 8 AN XY: 80412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000593

Gnomad NFE exome AF: 0.000148

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000887 AC: 123 AN: 1386848 Hom.: 0 Cov.: 56 AF XY: 0.0000729 AC XY: 50 AN XY: 685756

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.000835

Gnomad4 NFE exome AF: 0.0000776

Gnomad4 OTH exome AF: 0.000139

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152162 Hom.: 0 Cov.: 34 AF XY: 0.000108 AC XY: 8 AN XY: 74386

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000123 AC: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	1.7
DANN	Benign	0.66
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.39	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.67	T
REVEL	Benign	0.014
Sift4G	Benign	0.10	T;T
Polyphen		0.50	P;.
Vest4		0.094
MVP		0.42
MPC		0.35
ClinPred		0.054	T
GERP RS		-1.2
Varity_R		0.073
gMVP		0.096

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

Publications

LitVar

Other links and lift over

dbSNP: rs605059; hg19: chr17-40706906;