Genetic Variant HSD17B4:p.Met1? (chr5-119452578-G-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000414.4(HSD17B4):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

HSD17B4
NM_000414.4 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.81

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: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 40 pathogenic variants. Next in-frame start position is after 138 codons. Genomic position: 119477479. Lost 0.186 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-119452578-G-A is Pathogenic according to our data. Variant chr5-119452578-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 225388.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3G>A	p.Met1?	start_lost	Exon 1 of 24	NP_000405.1	A0A0S2Z4J1
HSD17B4	NM_001374497.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 24	NP_001361426.1
HSD17B4	NM_001199292.2		c.3G>A	p.Met1?	start_lost	Exon 1 of 23	NP_001186221.1	P51659-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 24	ENSP00000424940.3	P51659-1
HSD17B4	ENST00000509514.6	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 1 of 24	ENSP00000426272.2	E7EPL9
HSD17B4	ENST00000515320.5	TSL:2	c.3G>A	p.Met1?	start_lost	Exon 1 of 23	ENSP00000424613.1	P51659-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.32

PhyloP100

2.8

PROVEAN

Benign

-1.4

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.040

Polyphen

1.0

Vest4

0.77

MutPred

0.97

Loss of MoRF binding (P = 0.0963)

MVP

0.85

ClinPred

1.0

GERP RS

5.0

PromoterAI

-0.20

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.95

Mutation Taster

=6/194

disease causing (ClinVar)

(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