Genetic Variant HSD17B4:p.Gln677Glu (chr5-119536458-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000414.4(HSD17B4):c.2029C>G(p.Gln677Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

HSD17B4
NM_000414.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.21

Publications

0 publications found

Variant links:

Genes affected

HSD17B4 (HGNC:5213): (hydroxysteroid 17-beta dehydrogenase 4) The protein encoded by this gene is a bifunctional enzyme that is involved in the peroxisomal beta-oxidation pathway for fatty acids. It also acts as a catalyst for the formation of 3-ketoacyl-CoA intermediates from both straight-chain and 2-methyl-branched-chain fatty acids. Defects in this gene that affect the peroxisomal fatty acid beta-oxidation activity are a cause of D-bifunctional protein deficiency (DBPD). An apparent pseudogene of this gene is present on chromosome 8. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

HSD17B4 Gene-Disease associations (from GenCC):

d-bifunctional protein deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
Perrault syndrome
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Perrault syndrome 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

HSD17B4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28296173).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000414.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSD17B4	NM_000414.4	MANE Select	c.2029C>G	p.Gln677Glu	missense	Exon 23 of 24	NP_000405.1	A0A0S2Z4J1
HSD17B4	NM_001199291.3		c.2104C>G	p.Gln702Glu	missense	Exon 24 of 25	NP_001186220.1	P51659-2
HSD17B4	NM_001374497.1		c.2020C>G	p.Gln674Glu	missense	Exon 23 of 24	NP_001361426.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.2029C>G	p.Gln677Glu	missense	Exon 23 of 24	ENSP00000424940.3	P51659-1
HSD17B4	ENST00000509514.6	TSL:1	c.1960C>G	p.Gln654Glu	missense	Exon 23 of 24	ENSP00000426272.2	E7EPL9
HSD17B4	ENST00000414835.7	TSL:2	c.2104C>G	p.Gln702Glu	missense	Exon 24 of 25	ENSP00000411960.3	P51659-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.052

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

M_CAP

Benign

0.0056

MetaRNN

Benign

0.28

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

PhyloP100

2.2

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.71

REVEL

Benign

0.030

Sift

Benign

0.41

Sift4G

Benign

0.77

Polyphen

0.016

Vest4

0.21

MutPred

0.46

Gain of ubiquitination at K674 (P = 0.0463)

MVP

0.25

MPC

0.066

ClinPred

0.53

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.37

Mutation Taster

=80/20

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over