5-119476485-A-G

Variant names:

• chr5-119476485-A-G
• rs2678070
• NM_000414.4:c.349+615A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000414.4(HSD17B4):​c.349+615A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 799,560 control chromosomes in the GnomAD database, including 97,046 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (20928 hom., cov: 31)
  • Exomes 𝑓: 0.48 (76118 hom.)
• Consequence: HSD17B4 NM_000414.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.352
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	NM_000414.4	MANE Select	c.349+615A>G		intron	N/A	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001199291.3		c.424+615A>G		intron	N/A	NP_001186220.1	P51659-2
	HSD17B4	NM_001374497.1		c.349+615A>G		intron	N/A	NP_001361426.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.349+615A>G		intron	N/A	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.349+615A>G		intron	N/A	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000414835.7	TSL:2	c.424+615A>G		intron	N/A	ENSP00000411960.3	P51659-2

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78629 AN: 151856 Hom.: 20898 Cov.: 31

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.922

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.537

GnomAD4 exome AF: 0.481 AC: 311733 AN: 647586 Hom.: 76118 Cov.: 8 AF XY: 0.480 AC XY: 145108 AN XY: 301996

African (AFR) AF: 0.500 AC: 5954 AN: 11902

American (AMR) AF: 0.566 AC: 455 AN: 804

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 2161 AN: 4038

East Asian (EAS) AF: 0.927 AC: 2526 AN: 2724

South Asian (SAS) AF: 0.497 AC: 6274 AN: 12620

European-Finnish (FIN) AF: 0.608 AC: 135 AN: 222

Middle Eastern (MID) AF: 0.536 AC: 691 AN: 1288

European-Non Finnish (NFE) AF: 0.477 AC: 283092 AN: 592890

Other (OTH) AF: 0.495 AC: 10445 AN: 21098

GnomAD4 genome AF: 0.518 AC: 78712 AN: 151974 Hom.: 20928 Cov.: 31 AF XY: 0.524 AC XY: 38915 AN XY: 74280

African (AFR) AF: 0.493 AC: 20423 AN: 41458

American (AMR) AF: 0.530 AC: 8082 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1919 AN: 3466

East Asian (EAS) AF: 0.923 AC: 4786 AN: 5188

South Asian (SAS) AF: 0.529 AC: 2552 AN: 4828

European-Finnish (FIN) AF: 0.549 AC: 5782 AN: 10540

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33293 AN: 67930

Other (OTH) AF: 0.534 AC: 1126 AN: 2108

Alfa AF: 0.496 Hom.: 31715

Bravo AF: 0.519

Asia WGS AF: 0.678 AC: 2351 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	5.8
DANN	Benign	0.74
PhyloP100		0.35
PromoterAI		0.026	Neutral
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: rs2678070; hg19: chr5-118812180;