NM_000413.4:c.311G>T

Variant names:

• chr17-42553484-G-T
• NM_000413.4:c.311G>T

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.311G>T​(p.Gly104Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G104R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: HSD17B1 NM_000413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.308
• Publications: 0 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=0.120551825).

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.311G>T	p.Gly104Val	missense	Exon 3 of 6	NP_000404.2	P14061
	HSD17B1	NM_001330219.3		c.311G>T	p.Gly104Val	missense	Exon 3 of 6	NP_001317148.1	A0A0A0MQS7
	HSD17B1	NR_144397.2		n.322G>T		non_coding_transcript_exon	Exon 3 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B1	ENST00000585807.6	TSL:1 MANE Select	c.311G>T	p.Gly104Val	missense	Exon 3 of 6	ENSP00000466799.1	P14061
	HSD17B1	ENST00000225929.5	TSL:2	c.311G>T	p.Gly104Val	missense	Exon 3 of 6	ENSP00000225929.5	A0A0A0MQS7
	HSD17B1	ENST00000587280.1	TSL:2	n.469G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	4.1
DANN	Benign	0.87
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.31
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.22
Sift	Benign	0.054	T
Sift4G	Uncertain	0.042	D
Polyphen		0.041	B
Vest4		0.18
MutPred		0.47		Loss of loop (P = 0.0986)
MVP		0.72
MPC		0.40
ClinPred		0.065	T
GERP RS		-8.7
Varity_R		0.058
gMVP		0.54

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

hg19: chr17-40705502;