Genetic Variant HSD17B2:p.Thr140Met (chr16-82068323-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002153.3(HSD17B2):c.419C>T(p.Thr140Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,902 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

HSD17B2
NM_002153.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.08

Publications

1 publications found

Variant links:

Genes affected

HSD17B2 (HGNC:5211): (hydroxysteroid 17-beta dehydrogenase 2) Enables estradiol 17-beta-dehydrogenase activity and testosterone dehydrogenase (NAD+) activity. Involved in response to retinoic acid. Predicted to be located in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

HSD17B2 links:

HSD17B2-AS1 (HGNC:56281): (HSD17B2 antisense RNA 1)

HSD17B2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002153.3. 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
	HSD17B2	NM_002153.3	MANE Select	c.419C>T	p.Thr140Met	missense	Exon 2 of 5	NP_002144.1	P37059

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSD17B2	ENST00000199936.9	TSL:1 MANE Select	c.419C>T	p.Thr140Met	missense	Exon 2 of 5	ENSP00000199936.4	P37059
HSD17B2	ENST00000891334.1		c.419C>T	p.Thr140Met	missense	Exon 3 of 6	ENSP00000561393.1
HSD17B2	ENST00000891335.1		c.419C>T	p.Thr140Met	missense	Exon 3 of 6	ENSP00000561394.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251206

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461736

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111970

Other (OTH)

AF:

0.0000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.775

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.013

MutationAssessor

Pathogenic

3.0

PhyloP100

7.1

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.47

Sift

Uncertain

0.023

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.91

MutPred

0.72

Loss of methylation at K141 (P = 0.0388)

MVP

0.96

MPC

0.026

ClinPred

0.97

GERP RS

5.2

PromoterAI

0.031

Neutral

(source)

Varity_R

0.80

gMVP

0.62

Mutation Taster

=39/61

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over