Genetic Variant NM_178135.5:c.532G>C (chr4-87315518-C-G) – 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_178135.5(HSD17B13):c.532G>C(p.Gly178Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HSD17B13
NM_178135.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.00

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: 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B13	NM_178135.5 link	c.532G>C	p.Gly178Arg	missense_variant	Exon 4 of 7	ENST00000328546.5	NP_835236.2	Q7Z5P4-1
HSD17B13	NM_001136230.3 link	c.424G>C	p.Gly142Arg	missense_variant	Exon 3 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.532G>C	p.Gly178Arg	missense_variant	Exon 4 of 7	1	NM_178135.5	ENSP00000333300.4		Q7Z5P4-1
HSD17B13	ENST00000302219.10 link	c.424G>C	p.Gly142Arg	missense_variant	Exon 3 of 6	1		ENSP00000305438.6		Q7Z5P4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458146

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44586

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

86016

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1109060

Other (OTH)

AF:

0.00

AC:

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

.;T

Eigen

Benign

0.12

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.51

T;T

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.39

MutationAssessor

Pathogenic

3.6

.;H

PhyloP100

1.0

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Uncertain

0.46

Sift

Benign

0.064

T;T

Sift4G

Uncertain

0.035

D;D

Polyphen

0.85

P;P

Vest4

0.54

MutPred

0.83

.;Gain of solvent accessibility (P = 0.0306);

MVP

0.95

MPC

0.47

ClinPred

0.90

GERP RS

3.4

Varity_R

0.19

gMVP

0.61

Mutation Taster

=99/1

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over