chr9-96235528-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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B3	NM_000197.2	c.865G>T	p.Gly289Cys	missense_variant	Exon 11 of 11	ENST00000375263.8	NP_000188.1
SLC35D2-HSD17B3	NR_182427.1	n.3632G>T		non_coding_transcript_exon_variant	Exon 26 of 26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B3	ENST00000375263.8	c.865G>T	p.Gly289Cys	missense_variant	Exon 11 of 11	1	NM_000197.2	ENSP00000364412.3
ENSG00000285269	ENST00000643789.1	n.*2541G>T		non_coding_transcript_exon_variant	Exon 22 of 22			ENSP00000494818.1
ENSG00000285269	ENST00000643789.1	n.*2541G>T		3_prime_UTR_variant	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 v4.3

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;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		-0.41
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.047	D;D
Sift4G	Uncertain	0.048	D;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;