9-96235528-C-A

Variant names:

• chr9-96235528-C-A
• rs2066479
• NM_000197.2:c.865G>T

Variant summary

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

The NM_000197.2(HSD17B3):​c.865G>T​(p.Gly289Cys) 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. 15/22 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. G289S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HSD17B3 NM_000197.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.410
• Publications: 47 publications found

Genes affected

HSD17B3 (HGNC:5212): (hydroxysteroid 17-beta dehydrogenase 3) This isoform of 17 beta-hydroxysteroid dehydrogenase is expressed predominantly in the testis and catalyzes the conversion of androstenedione to testosterone. It preferentially uses NADP as cofactor. Deficiency can result in male pseudohermaphroditism with gynecomastia. [provided by RefSeq, Jul 2008]

HSD17B3 Gene-Disease associations (from GenCC):

• 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000285269 (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=0.14333957).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000197.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	NM_000197.2	MANE Select	c.865G>T	p.Gly289Cys	missense	Exon 11 of 11	NP_000188.1
	SLC35D2-HSD17B3	NR_182427.1		n.3632G>T		non_coding_transcript_exon	Exon 26 of 26

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	ENST00000375263.8	TSL:1 MANE Select	c.865G>T	p.Gly289Cys	missense	Exon 11 of 11	ENSP00000364412.3
	HSD17B3	ENST00000375262.4	TSL:1	c.715G>T	p.Gly239Cys	missense	Exon 10 of 10	ENSP00000364411.2
	ENSG00000285269	ENST00000643789.1		n.*2541G>T		non_coding_transcript_exon	Exon 22 of 22	ENSP00000494818.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.9
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.41
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.38
Sift	Benign	0.047	D
Sift4G	Uncertain	0.048	D
Polyphen		0.99	D
Vest4		0.15
MutPred		0.22		Loss of glycosylation at S288 (P = 0.0461)
MVP		0.76
MPC		0.31
ClinPred		0.34	T
GERP RS		-5.2
Varity_R		0.077
gMVP		0.54
Mutation Taster		=98/2	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: rs2066479; hg19: chr9-98997810;