Genetic Variant HSD17B4:p.Gln677Lys (chr5-119536458-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000414.4(HSD17B4):c.2029C>A(p.Gln677Lys) 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23178557).

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>A	p.Gln677Lys	missense	Exon 23 of 24	NP_000405.1	A0A0S2Z4J1
HSD17B4	NM_001199291.3		c.2104C>A	p.Gln702Lys	missense	Exon 24 of 25	NP_001186220.1	P51659-2
HSD17B4	NM_001374497.1		c.2020C>A	p.Gln674Lys	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>A	p.Gln677Lys	missense	Exon 23 of 24	ENSP00000424940.3	P51659-1
HSD17B4	ENST00000509514.6	TSL:1	c.1960C>A	p.Gln654Lys	missense	Exon 23 of 24	ENSP00000426272.2	E7EPL9
HSD17B4	ENST00000414835.7	TSL:2	c.2104C>A	p.Gln702Lys	missense	Exon 24 of 25	ENSP00000411960.3	P51659-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.038

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.79

M_CAP

Benign

0.0055

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.29

PhyloP100

2.2

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.10

REVEL

Benign

0.050

Sift

Benign

0.58

Sift4G

Benign

1.0

Polyphen

0.0050

Vest4

0.14

MutPred

0.46

Loss of ubiquitination at K674 (P = 0.0258)

MVP

0.24

MPC

0.075

ClinPred

0.55

GERP RS

4.0

Varity_R

0.22

gMVP

0.38

Mutation Taster

=73/27

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