NM_000197.2:c.822+855G>A

Variant names:

• chr9-96239903-C-T
• rs8190560
• NM_000197.2:c.822+855G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000197.2(HSD17B3):​c.822+855G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 152,304 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.034 (225 hom., cov: 33)
  • Exomes 𝑓: 0.029 (0 hom.)
• Consequence: HSD17B3 NM_000197.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.659
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	NM_000197.2	MANE Select	c.822+855G>A		intron	N/A	NP_000188.1
	SLC35D2-HSD17B3	NR_182427.1		n.3589+855G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B3	ENST00000375263.8	TSL:1 MANE Select	c.822+855G>A		intron	N/A	ENSP00000364412.3
	HSD17B3	ENST00000375262.4	TSL:1	c.673-4333G>A		intron	N/A	ENSP00000364411.2
	ENSG00000285269	ENST00000643789.1		n.*2498+855G>A		intron	N/A	ENSP00000494818.1

Frequencies

GnomAD3 genomes AF: 0.0341 AC: 5193 AN: 152150 Hom.: 222 Cov.: 33

Gnomad AFR AF: 0.00645

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.0800

Gnomad SAS AF: 0.0680

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0235

Gnomad OTH AF: 0.0344

GnomAD4 exome AF: 0.0294 AC: 1 AN: 34 Hom.: 0 Cov.: 0 AF XY: 0.0385 AC XY: 1 AN XY: 26

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0313 AC: 1 AN: 32

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0342 AC: 5206 AN: 152270 Hom.: 225 Cov.: 33 AF XY: 0.0380 AC XY: 2832 AN XY: 74438

African (AFR) AF: 0.00643 AC: 267 AN: 41548

American (AMR) AF: 0.123 AC: 1888 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 96 AN: 3470

East Asian (EAS) AF: 0.0799 AC: 414 AN: 5180

South Asian (SAS) AF: 0.0684 AC: 330 AN: 4822

European-Finnish (FIN) AF: 0.0444 AC: 471 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0235 AC: 1598 AN: 68030

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

Alfa AF: 0.0341 Hom.: 24

Bravo AF: 0.0391

Asia WGS AF: 0.0790 AC: 273 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.12
DANN	Benign	0.30
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8190560; hg19: chr9-99002185;