rs190659146

Variant names:

• chr5-119527227-T-C
• rs190659146
• NM_000414.4:c.1767+8T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-119527227-T-C
• chr5-119527227-T-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000414.4(HSD17B4):​c.1767+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 0.00254 in 1,571,114 control chromosomes in the GnomAD database, including 120 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (114 hom.)
• Consequence: HSD17B4 NM_000414.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003647
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.143
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-119527227-T-C is Benign according to our data. Variant chr5-119527227-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00172 (262/152146) while in subpopulation SAS AF = 0.0485 (234/4822). AF 95% confidence interval is 0.0434. There are 6 homozygotes in GnomAd4. There are 196 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	NM_000414.4	MANE Select	c.1767+8T>C		splice_region intron	N/A	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001199291.3		c.1842+8T>C		splice_region intron	N/A	NP_001186220.1	P51659-2
	HSD17B4	NM_001374497.1		c.1758+8T>C		splice_region 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.1767+8T>C		splice_region intron	N/A	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.1698+8T>C		splice_region intron	N/A	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000414835.7	TSL:2	c.1842+8T>C		splice_region intron	N/A	ENSP00000411960.3	P51659-2

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 263 AN: 152028 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.0487

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00564 AC: 1413 AN: 250556 AF XY: 0.00724

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00299

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00262 AC: 3723 AN: 1418968 Hom.: 114 Cov.: 25 AF XY: 0.00372 AC XY: 2638 AN XY: 708548

African (AFR) AF: 0.0000921 AC: 3 AN: 32558

American (AMR) AF: 0.0000674 AC: 3 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25780

East Asian (EAS) AF: 0.00221 AC: 87 AN: 39336

South Asian (SAS) AF: 0.0400 AC: 3410 AN: 85256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00198 AC: 11 AN: 5562

European-Non Finnish (NFE) AF: 0.0000345 AC: 37 AN: 1073722

Other (OTH) AF: 0.00292 AC: 172 AN: 58892

GnomAD4 genome AF: 0.00172 AC: 262 AN: 152146 Hom.: 6 Cov.: 32 AF XY: 0.00263 AC XY: 196 AN XY: 74400

African (AFR) AF: 0.0000481 AC: 2 AN: 41546

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00347 AC: 18 AN: 5190

South Asian (SAS) AF: 0.0485 AC: 234 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67920

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000377 Hom.: 0

Bravo AF: 0.000450

Asia WGS AF: 0.0140 AC: 47 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Bifunctional peroxisomal enzyme deficiency (2)
-	-	2	not specified (2)
-	-	1	Bifunctional peroxisomal enzyme deficiency;C0685838:Perrault syndrome (1)
-	-	1	HSD17B4-related disorder (1)
-	-	1	Perrault syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.63
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0
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: rs190659146; hg19: chr5-118862922;