rs119481080

Positions:

• chr9-96240777-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The ENST00000375263.8(HSD17B3):​c.803G>A​(p.Cys268Tyr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. C268C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSD17B3 ENST00000375263.8 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.83

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]

SLC35D2-HSD17B3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877
• PP5: Variant 9-96240777-C-T is Pathogenic according to our data. Variant chr9-96240777-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4881.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD17B3	NM_000197.2	c.803G>A	p.Cys268Tyr	missense_variant	10/11	ENST00000375263.8	NP_000188.1
SLC35D2-HSD17B3	NR_182427.1	n.3570G>A		non_coding_transcript_exon_variant	25/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B3	ENST00000375263.8	c.803G>A	p.Cys268Tyr	missense_variant	10/11	1	NM_000197.2	ENSP00000364412	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Testosterone 17-beta-dehydrogenase deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Biochemistry Laboratory, Health Services Laboratory	Nov 20, 2023	ACMG:PS3 PM1 PM2 PP2 PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Benign	0.77
DEOGEN2	Benign	0.15	T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.68	T;T
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.99	A;A
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.4	D;.
REVEL	Pathogenic	0.74
Sift	Benign	0.13	T;.
Sift4G	Benign	0.28	T;.
Polyphen		1.0	D;.
Vest4		0.77
MutPred		0.82		Loss of catalytic residue at L269 (P = 0.0439);.;
MVP		0.86
MPC		0.72
ClinPred		0.96	D
GERP RS		4.3
Varity_R		0.39
gMVP		0.78

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: rs119481080; hg19: chr9-99003059;