Genetic Variant HSD17B13:p.Ala191Val (chr4-87313946-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_178135.5(HSD17B13):c.572C>T(p.Ala191Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000283 in 1,411,790 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: not found (cov: 30)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

HSD17B13
NM_178135.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.24

Publications

0 publications found

Variant links:

Genes affected

HSD17B13 (HGNC:18685): (hydroxysteroid 17-beta dehydrogenase 13) Predicted to enable oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor and steroid dehydrogenase activity. Acts upstream of or within positive regulation of lipid biosynthetic process. Located in lipid droplet. [provided by Alliance of Genome Resources, Apr 2022]

HSD17B13 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B13	NM_178135.5 link	c.572C>T	p.Ala191Val	missense_variant	Exon 5 of 7	ENST00000328546.5	NP_835236.2	Q7Z5P4-1
HSD17B13	NM_001136230.3 link	c.464C>T	p.Ala155Val	missense_variant	Exon 4 of 6		NP_001129702.1	Q7Z5P4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B13	ENST00000328546.5 link	c.572C>T	p.Ala191Val	missense_variant	Exon 5 of 7	1	NM_178135.5	ENSP00000333300.4		Q7Z5P4-1
HSD17B13	ENST00000302219.10 link	c.464C>T	p.Ala155Val	missense_variant	Exon 4 of 6	1		ENSP00000305438.6		Q7Z5P4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1411790

Hom.:

Cov.:

AF XY:

0.00000427

AC XY:

AN XY:

701790

show subpopulations

African (AFR)

AF:

0.000100

AC:

AN:

30004

American (AMR)

AF:

0.00

AC:

AN:

37230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24462

East Asian (EAS)

AF:

0.00

AC:

AN:

36592

South Asian (SAS)

AF:

0.00

AC:

AN:

79356

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1088648

Other (OTH)

AF:

0.00

AC:

AN:

57798

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.572C>T (p.A191V) alteration is located in exon 5 (coding exon 5) of the HSD17B13 gene. This alteration results from a C to T substitution at nucleotide position 572, causing the alanine (A) at amino acid position 191 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

.;D

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.1

.;H

PhyloP100

5.2

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.70

MutPred

0.73

.;Loss of ubiquitination at K189 (P = 0.0768);

MVP

0.99

MPC

0.36

ClinPred

0.99

GERP RS

3.8

Varity_R

0.27

gMVP

0.74

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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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4-87313946-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over