9-96235569-G-A

Variant names:

• chr9-96235569-G-A
• rs751855814
• NM_000197.2:c.824C>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.824C>T​(p.Ala275Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,612,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A275A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: HSD17B3 NM_000197.2 missense, splice_region
• Scores: Splicing: ADA: 0.0001982
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.835
• Publications: 1 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: 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=0.16527829).

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.824C>T	p.Ala275Val	missense splice_region	Exon 11 of 11	NP_000188.1	P37058-1
	SLC35D2-HSD17B3	NR_182427.1		n.3591C>T		splice_region non_coding_transcript_exon	Exon 26 of 26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	ENST00000375263.8	TSL:1 MANE Select	c.824C>T	p.Ala275Val	missense splice_region	Exon 11 of 11	ENSP00000364412.3	P37058-1
	HSD17B3	ENST00000375262.4	TSL:1	c.674C>T	p.Ala225Val	missense splice_region	Exon 10 of 10	ENSP00000364411.2	P37058-2
	ENSG00000285269	ENST00000643789.1		n.*2500C>T		splice_region non_coding_transcript_exon	Exon 22 of 22	ENSP00000494818.1	A0A2R8Y5X9

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000320 AC: 8 AN: 249800 AF XY: 0.0000370

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1460298 Hom.: 0 Cov.: 30 AF XY: 0.0000523 AC XY: 38 AN XY: 726476

African (AFR) AF: 0.0000598 AC: 2 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26108

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000639 AC: 71 AN: 1110936

Other (OTH) AF: 0.0000331 AC: 2 AN: 60342

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

African (AFR) AF: 0.0000241 AC: 1 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000904 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.83
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.34
Sift	Benign	0.15	T
Sift4G	Benign	0.24	T
Polyphen		0.028	B
Vest4		0.19
MutPred		0.51		Loss of glycosylation at S279 (P = 0.2017)
MVP		0.82
MPC		0.18
ClinPred		0.12	T
GERP RS		0.66
Varity_R		0.033
gMVP		0.62
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.052
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: rs751855814; hg19: chr9-98997851; COSMIC: COSV64558708; COSMIC: COSV64558708;