5-119489235-C-T

Variant names:

• chr5-119489235-C-T
• rs150677536
• NM_000414.4:c.666C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_000414.4(HSD17B4):​c.666C>T​(p.Val222Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,612,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V222V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: HSD17B4 NM_000414.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: -0.956
• Publications: 1 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 5-119489235-C-T is Benign according to our data. Variant chr5-119489235-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 764144.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.956 with no splicing effect.

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.666C>T	p.Val222Val	synonymous	Exon 9 of 24	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001199291.3		c.741C>T	p.Val247Val	synonymous	Exon 10 of 25	NP_001186220.1	P51659-2
	HSD17B4	NM_001374497.1		c.657C>T	p.Val219Val	synonymous	Exon 9 of 24	NP_001361426.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.666C>T	p.Val222Val	synonymous	Exon 9 of 24	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.666C>T	p.Val222Val	synonymous	Exon 9 of 24	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000414835.7	TSL:2	c.741C>T	p.Val247Val	synonymous	Exon 10 of 25	ENSP00000411960.3	P51659-2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251212 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1460560 Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 13 AN XY: 726608

African (AFR) AF: 0.00 AC: 0 AN: 33388

American (AMR) AF: 0.000381 AC: 17 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111072

Other (OTH) AF: 0.00 AC: 0 AN: 60300

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

African (AFR) AF: 0.0000482 AC: 2 AN: 41510

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	5.3
DANN	Benign	0.52
PhyloP100		-0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150677536; hg19: chr5-118824930;