17-42552940-C-G

Variant names:

• chr17-42552940-C-G
• rs61743701
• NM_000413.4:c.7C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000413.4(HSD17B1):​c.7C>G​(p.Arg3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R3C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HSD17B1 NM_000413.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11078504).

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.7C>G	p.Arg3Gly	missense	Exon 1 of 6	NP_000404.2	P14061
	HSD17B1	NM_001330219.3		c.7C>G	p.Arg3Gly	missense	Exon 1 of 6	NP_001317148.1	A0A0A0MQS7
	HSD17B1	NR_144397.2		n.18C>G		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B1	ENST00000585807.6	TSL:1 MANE Select	c.7C>G	p.Arg3Gly	missense	Exon 1 of 6	ENSP00000466799.1	P14061
	HSD17B1	ENST00000225929.5	TSL:2	c.7C>G	p.Arg3Gly	missense	Exon 1 of 6	ENSP00000225929.5	A0A0A0MQS7
	HSD17B1	ENST00000587280.1	TSL:2	n.18C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251052 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461606 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727102

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111914

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.99	N
PhyloP100		-0.24
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.15
Sift	Benign	0.16	T
Sift4G	Benign	0.37	T
Polyphen		0.017	B
Vest4		0.28
MutPred		0.42		Loss of stability (P = 0.0125)
MVP		0.70
MPC		0.48
ClinPred		0.15	T
GERP RS		2.1
PromoterAI		0.18	Neutral
Varity_R		0.27
gMVP		0.50
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs61743701; hg19: chr17-40704958;