rs119481076

Variant names:

• chr9-96244393-G-A
• rs119481076
• NM_000197.2:c.608C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-96244393-G-A
• chr9-96244393-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000197.2(HSD17B3):​c.608C>T​(p.Ala203Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000013 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A203A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: HSD17B3 NM_000197.2 missense, splice_region
• Scores: Splicing: ADA: 0.01508
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.71
• Publications: 13 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ENSG00000285269 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 9-96244393-G-A is Pathogenic according to our data. Variant chr9-96244393-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	NM_000197.2	MANE Select	c.608C>T	p.Ala203Val	missense splice_region	Exon 9 of 11	NP_000188.1	P37058-1
	SLC35D2-HSD17B3	NR_182427.1		n.3375C>T		splice_region non_coding_transcript_exon	Exon 24 of 26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	ENST00000375263.8	TSL:1 MANE Select	c.608C>T	p.Ala203Val	missense splice_region	Exon 9 of 11	ENSP00000364412.3	P37058-1
	HSD17B3	ENST00000375262.4	TSL:1	c.608C>T	p.Ala203Val	missense splice_region	Exon 9 of 10	ENSP00000364411.2	P37058-2
	ENSG00000285269	ENST00000643789.1		n.*2284C>T		splice_region non_coding_transcript_exon	Exon 20 of 22	ENSP00000494818.1	A0A2R8Y5X9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251466 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461842 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727228

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111970

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000193 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Pseudohermaphroditism (1)
1	-	-	Testosterone 17-beta-dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.7
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N
REVEL	Pathogenic	0.67
Sift	Benign	0.31	T
Sift4G	Benign	0.54	T
Polyphen		0.71	P
Vest4		0.59
MutPred		0.94		Gain of methylation at K202 (P = 0.0678)
MVP		0.94
MPC		0.23
ClinPred		0.62	D
GERP RS		4.8
Varity_R		0.27
gMVP		0.86
Mutation Taster		=79/21	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.15
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

dbSNP: rs119481076; hg19: chr9-99006675; COSMIC: COSV100931226; COSMIC: COSV100931226;