9-96298423-G-A

Position:

• chr9-96298423-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Moderate

The NM_000197.2(HSD17B3):​c.194C>T​(p.Ser65Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. S65S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: HSD17B3 NM_000197.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.42

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 Pathogenic. Variant got 12 ACMG points.

• PS1: Transcript NM_000197.2 (HSD17B3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a binding_site (size 29) in uniprot entity DHB3_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000197.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 9-96298423-G-A is Pathogenic according to our data. Variant chr9-96298423-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242504.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-96298423-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD17B3	NM_000197.2	c.194C>T	p.Ser65Leu	missense_variant	2/11	ENST00000375263.8	NP_000188.1
SLC35D2-HSD17B3	NR_182427.1	n.2961C>T		non_coding_transcript_exon_variant	17/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B3	ENST00000375263.8	c.194C>T	p.Ser65Leu	missense_variant	2/11	1	NM_000197.2	ENSP00000364412	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251432 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461054 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 726914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Testosterone 17-beta-dehydrogenase deficiency Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.194C>T p.Ser65Leu variant in HSD17B3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser65Leu variant has allele frequency 0.001% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid change p.Ser65Leu in HSD17B3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 65 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	-0.058	T
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.1	D;D;.;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Uncertain	0.0030	D;D;.;.
Polyphen		0.68	P;.;.;.
Vest4		0.75
MutPred		0.93		Loss of disorder (P = 0.0768);Loss of disorder (P = 0.0768);Loss of disorder (P = 0.0768);Loss of disorder (P = 0.0768);
MVP		0.91
MPC		0.40
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.56
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs747329682; hg19: chr9-99060705; COSMIC: COSV64556553;