NM_000414.4:c.2199C>T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000414.4(HSD17B4):​c.2199C>T​(p.Tyr733Tyr) 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_000414.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.408

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4	c.2199C>T	p.Tyr733Tyr	synonymous_variant	Exon 24 of 24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7	c.2199C>T	p.Tyr733Tyr	synonymous_variant	Exon 24 of 24	2	NM_000414.4	ENSP00000424940.3

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

GnomAD3 exomes AF: 0.0152 AC: 3806 AN: 251184 Hom.: 182 AF XY: 0.0143 AC XY: 1937 AN XY: 135756

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 SAS exome AF: 0.0439

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

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.00663

Gnomad4 ASJ exome AF: 0.00878

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0414

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.0118

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

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0478

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0164 Hom.: 62

Bravo AF: 0.0402

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00196

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tyr758Tyr in exon 25 of HSD17B4: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 11.2% (492/4404) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12714). -

not provided Benign:2

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 24, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bifunctional peroxisomal enzyme deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Perrault syndrome 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	1.9
DANN	Benign	0.37

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

LitVar

Other links and lift over

dbSNP: rs12714; hg19: chr5-118877677;