9-96235569-G-T

Variant names:

• chr9-96235569-G-T
• rs751855814
• NM_000197.2:c.824C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000197.2(HSD17B3):​c.824C>A​(p.Ala275Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. A275V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HSD17B3 NM_000197.2 missense, splice_region
• Scores: Splicing: ADA: 0.00004152
• Clinical Significance: Not reported in ClinVar
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000285269 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B3	NM_000197.2	c.824C>A	p.Ala275Glu	missense_variant, splice_region_variant	Exon 11 of 11	ENST00000375263.8	NP_000188.1
SLC35D2-HSD17B3	NR_182427.1	n.3591C>A		splice_region_variant, 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.824C>A	p.Ala275Glu	missense_variant, splice_region_variant	Exon 11 of 11	1	NM_000197.2	ENSP00000364412.3
ENSG00000285269	ENST00000643789.1	n.*2500C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 22 of 22			ENSP00000494818.1
ENSG00000285269	ENST00000643789.1	n.*2500C>A		3_prime_UTR_variant	Exon 22 of 22			ENSP00000494818.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.18	T;.;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.8	M;.;.
PhyloP100		0.83
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N;.
REVEL	Uncertain	0.49
Sift	Benign	0.19	T;D;.
Sift4G	Benign	0.79	T;D;.
Polyphen		0.47	P;.;.
Vest4		0.45
MutPred		0.62		Gain of relative solvent accessibility (P = 0.09);.;.;
MVP		0.88
MPC		0.49
ClinPred		0.89	D
GERP RS		0.66
Varity_R		0.066
gMVP		0.80
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.10		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;