NM_000414.4:c.46G>A

Variant names:

• chr5-119452621-G-A
• rs137853096
• NM_000414.4:c.46G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PP3_Strong PP5

The NM_000414.4(HSD17B4):​c.46G>A​(p.Gly16Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000328 in 1,613,836 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV002573283: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:10419023 , 10497229 , 9482850).; SCV000617161: Published functional studies demonstrate variant inactivates the 3-hydroxyacyl-CoA dehydrogenase component of the D-bifunctional protein (van Grunsven et al., 1998); SCV002064376: Expression studies in yeast showed that this mutant causes loss of the 3-hydroxyacyl-CoA dehydrogenase activity, an essential component of d-bifunctional protein (PMID:9482850).; SCV000816576: Experimental studies have shown that this missense change affects HSD17B4 function (PMID:9482850, 10419023, 10497229).; SCV000916080: Functional studies in yeast expressing the variant and wild type protein showed loss of 3-hydroxyacyl-CoA dehydrogenase activity, but did not affect the enoyl-CoA hydratase activity (van Grunsven et al. 1998).; SCV004736381: "This variant is known to be causative for D-bifunctional protein deficiency and Perrault syndrome, with functional experiments showing this results in inactive dehydrogenase enzymatic activity (van Grunsven et al. 1998. PubMed ID: 9482850; Demain et al. 2016. PubMed ID: 26970254; Pronicka et al. 2016. PubMed ID: 27290639)."". Synonymous variant affecting the same amino acid position (i.e. G16G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:26 U:1 O:1
• Conservation: PhyloP100: 4.86
• Publications: 19 publications found

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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002573283: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10419023 , 10497229 , 9482850).; SCV000617161: Published functional studies demonstrate variant inactivates the 3-hydroxyacyl-CoA dehydrogenase component of the D-bifunctional protein (van Grunsven et al., 1998); SCV002064376: Expression studies in yeast showed that this mutant causes loss of the 3-hydroxyacyl-CoA dehydrogenase activity, an essential component of d-bifunctional protein (PMID: 9482850).; SCV000816576: Experimental studies have shown that this missense change affects HSD17B4 function (PMID: 9482850, 10419023, 10497229).; SCV000916080: Functional studies in yeast expressing the variant and wild type protein showed loss of 3-hydroxyacyl-CoA dehydrogenase activity, but did not affect the enoyl-CoA hydratase activity (van Grunsven et al. 1998).; SCV004736381: "This variant is known to be causative for D-bifunctional protein deficiency and Perrault syndrome, with functional experiments showing this results in inactive dehydrogenase enzymatic activity (van Grunsven et al. 1998. PubMed ID: 9482850; Demain et al. 2016. PubMed ID: 26970254; Pronicka et al. 2016. PubMed ID: 27290639)."
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957
• PP5: Variant 5-119452621-G-A is Pathogenic according to our data. Variant chr5-119452621-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 7655.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	NM_000414.4	MANE Select	c.46G>A	p.Gly16Ser	missense	Exon 1 of 24	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001374497.1		c.46G>A	p.Gly16Ser	missense	Exon 1 of 24	NP_001361426.1
	HSD17B4	NM_001199292.2		c.46G>A	p.Gly16Ser	missense	Exon 1 of 23	NP_001186221.1	P51659-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.46G>A	p.Gly16Ser	missense	Exon 1 of 24	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.46G>A	p.Gly16Ser	missense	Exon 1 of 24	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000515320.5	TSL:2	c.46G>A	p.Gly16Ser	missense	Exon 1 of 23	ENSP00000424613.1	P51659-3

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000200 AC: 50 AN: 250088 AF XY: 0.000229

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000400

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000344 AC: 503 AN: 1461646 Hom.: 0 Cov.: 34 AF XY: 0.000336 AC XY: 244 AN XY: 727144

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.000436 AC: 485 AN: 1111940

Other (OTH) AF: 0.000215 AC: 13 AN: 60374

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74330

African (AFR) AF: 0.000145 AC: 6 AN: 41460

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68028

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000421 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
11	1	-	Bifunctional peroxisomal enzyme deficiency (12)
10	-	-	not provided (10)
2	-	-	HSD17B4-related disorder (2)
1	-	-	Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome (1)
1	-	-	Bifunctional peroxisomal enzyme deficiency;C4551721:Perrault syndrome 1 (1)
1	-	-	Perrault syndrome 1 (1)
-	-	-	Perrault syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		4.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.96
ClinPred		0.81	D
GERP RS		4.7
PromoterAI		-0.061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.98
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137853096; hg19: chr5-118788316;