Genetic Variant NM_000414.4:c.2199C>T (chr5-119541982-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.408

Publications

2 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: 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

HSD17B4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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_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
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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00767

AC XY:

5562

AN XY:

725182

show subpopulations

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:

AN:

39624

South Asian (SAS)

AF:

0.0414

AC:

3566

AN:

86148

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.0165

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00112

AC:

1238

AN:

1108186

Other (OTH)

AF:

0.0118

AC:

713

AN:

60180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

485

970

1456

1941

2426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0366

AC:

5574

AN:

152130

Hom.:

296

Cov.:

AF XY:

0.0361

AC XY:

2681

AN XY:

74368

show subpopulations

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:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0478

AC:

230

AN:

4816

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00151

AC:

103

AN:

68006

Other (OTH)

AF:

0.0279

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

264

529

793

1058

1322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0173

Hom.:

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

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Bifunctional peroxisomal enzyme deficiency (1)

Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome (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

(source)

DANN

Benign

0.37

PhyloP100

-0.41

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over