NM_000414.4:c.1210-8T>C

Variant names:

• chr5-119502033-T-C
• rs34254740
• NM_000414.4:c.1210-8T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000414.4(HSD17B4):​c.1210-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,596,748 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (6 hom.)
• Consequence: HSD17B4 NM_000414.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006648
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 1.06
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-119502033-T-C is Benign according to our data. Variant chr5-119502033-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227432.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00118 (180/152306) while in subpopulation NFE AF = 0.00206 (140/68002). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	NM_000414.4	MANE Select	c.1210-8T>C		splice_region intron	N/A	NP_000405.1
	HSD17B4	NM_001199291.3		c.1285-8T>C		splice_region intron	N/A	NP_001186220.1
	HSD17B4	NM_001374497.1		c.1201-8T>C		splice_region intron	N/A	NP_001361426.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.1210-8T>C		splice_region intron	N/A	ENSP00000424940.3
	HSD17B4	ENST00000509514.6	TSL:1	c.1210-8T>C		splice_region intron	N/A	ENSP00000426272.2
	HSD17B4	ENST00000414835.7	TSL:2	c.1285-8T>C		splice_region intron	N/A	ENSP00000411960.3

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00114 AC: 287 AN: 250980 AF XY: 0.00111

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000879

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00155 AC: 2242 AN: 1444442 Hom.: 6 Cov.: 27 AF XY: 0.00152 AC XY: 1094 AN XY: 719750

African (AFR) AF: 0.000181 AC: 6 AN: 33096

American (AMR) AF: 0.000179 AC: 8 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.00 AC: 0 AN: 85840

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00192 AC: 2110 AN: 1096404

Other (OTH) AF: 0.00107 AC: 64 AN: 59770

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74480

African (AFR) AF: 0.000481 AC: 20 AN: 41578

American (AMR) AF: 0.000458 AC: 7 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00102

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000874

EpiControl AF: 0.00178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (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	-0.85
CADD	Benign	1.9
DANN	Benign	0.57
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0020
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: rs34254740; hg19: chr5-118837728;