rs12714

Variant names:

• chr5-119541982-C-T
• rs12714
• NM_000414.4:c.2199C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001199291.3(HSD17B4):​c.2274C>T​(p.Tyr758Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00987 in 1,609,234 control chromosomes in the GnomAD database, including 711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (296 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (415 hom.)
• Consequence: HSD17B4 NM_001199291.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.408
• Publications: 2 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: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Perrault syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Perrault syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 5-119541982-C-T is Benign according to our data. Variant chr5-119541982-C-T is described in ClinVar as Benign. ClinVar VariationId is 226671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.408 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199291.3. 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.2199C>T	p.Tyr733Tyr	synonymous	Exon 24 of 24	NP_000405.1
	HSD17B4	NM_001199291.3		c.2274C>T	p.Tyr758Tyr	synonymous	Exon 25 of 25	NP_001186220.1
	HSD17B4	NM_001374497.1		c.2190C>T	p.Tyr730Tyr	synonymous	Exon 24 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.2199C>T	p.Tyr733Tyr	synonymous	Exon 24 of 24	ENSP00000424940.3
	HSD17B4	ENST00000509514.6	TSL:1	c.2130C>T	p.Tyr710Tyr	synonymous	Exon 24 of 24	ENSP00000426272.2
	HSD17B4	ENST00000414835.7	TSL:2	c.2274C>T	p.Tyr758Tyr	synonymous	Exon 25 of 25	ENSP00000411960.3

Frequencies

GnomAD3 genomes AF: 0.0365 AC: 5548 AN: 152012 Hom.: 293 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0125

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0477

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.0267

GnomAD2 exomes AF: 0.0152 AC: 3806 AN: 251184 AF XY: 0.0143

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00636

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00708 AC: 10314 AN: 1457104 Hom.: 415 Cov.: 29 AF XY: 0.00767 AC XY: 5562 AN XY: 725182

African (AFR) AF: 0.126 AC: 4159 AN: 33130

American (AMR) AF: 0.00663 AC: 296 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00878 AC: 229 AN: 26068

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39624

South Asian (SAS) AF: 0.0414 AC: 3566 AN: 86148

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53390

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5758

European-Non Finnish (NFE) AF: 0.00112 AC: 1238 AN: 1108186

Other (OTH) AF: 0.0118 AC: 713 AN: 60180

GnomAD4 genome AF: 0.0366 AC: 5574 AN: 152130 Hom.: 296 Cov.: 32 AF XY: 0.0361 AC XY: 2681 AN XY: 74368

African (AFR) AF: 0.119 AC: 4942 AN: 41480

American (AMR) AF: 0.0125 AC: 191 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0478 AC: 230 AN: 4816

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10588

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00151 AC: 103 AN: 68006

Other (OTH) AF: 0.0279 AC: 59 AN: 2116

Alfa AF: 0.0173 Hom.: 68

Bravo AF: 0.0402

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00196

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Bifunctional peroxisomal enzyme deficiency (1)
-	-	1	Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome (1)
-	-	1	Perrault syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.9
DANN	Benign	0.37
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs12714; hg19: chr5-118877677;