5-119452501-C-G

Variant names:

• chr5-119452501-C-G
• rs26180
• NM_000414.4:c.-75C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000414.4(HSD17B4):​c.-75C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 1,610,302 control chromosomes in the GnomAD database, including 183,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15155 hom., cov: 33)
  • Exomes 𝑓: 0.48 (168189 hom.)
• Consequence: HSD17B4 NM_000414.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0680
• Publications: 10 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=-0.76).
• BP6: Variant 5-119452501-C-G is Benign according to our data. Variant chr5-119452501-C-G is described in ClinVar as Benign. ClinVar VariationId is 350457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.486 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.-75C>G		5_prime_UTR	Exon 1 of 24	NP_000405.1	A0A0S2Z4J1
	HSD17B4	NM_001199291.3		c.-253C>G		5_prime_UTR	Exon 1 of 25	NP_001186220.1	P51659-2
	HSD17B4	NM_001374497.1		c.-75C>G		5_prime_UTR	Exon 1 of 24	NP_001361426.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.-75C>G		5_prime_UTR	Exon 1 of 24	ENSP00000424940.3	P51659-1
	HSD17B4	ENST00000509514.6	TSL:1	c.-75C>G		5_prime_UTR	Exon 1 of 24	ENSP00000426272.2	E7EPL9
	HSD17B4	ENST00000414835.7	TSL:2	c.-253C>G		5_prime_UTR	Exon 1 of 25	ENSP00000411960.3	P51659-2

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65737 AN: 151990 Hom.: 15142 Cov.: 33

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.499

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.464

GnomAD4 exome AF: 0.477 AC: 695856 AN: 1458194 Hom.: 168189 Cov.: 33 AF XY: 0.475 AC XY: 344384 AN XY: 725544

African (AFR) AF: 0.266 AC: 8899 AN: 33416

American (AMR) AF: 0.571 AC: 25449 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 14545 AN: 26106

East Asian (EAS) AF: 0.463 AC: 18371 AN: 39676

South Asian (SAS) AF: 0.374 AC: 32177 AN: 86132

European-Finnish (FIN) AF: 0.557 AC: 29589 AN: 53154

Middle Eastern (MID) AF: 0.481 AC: 2235 AN: 4646

European-Non Finnish (NFE) AF: 0.483 AC: 536672 AN: 1110292

Other (OTH) AF: 0.464 AC: 27919 AN: 60180

GnomAD4 genome AF: 0.432 AC: 65786 AN: 152108 Hom.: 15155 Cov.: 33 AF XY: 0.434 AC XY: 32290 AN XY: 74354

African (AFR) AF: 0.273 AC: 11322 AN: 41514

American (AMR) AF: 0.495 AC: 7565 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1901 AN: 3472

East Asian (EAS) AF: 0.499 AC: 2563 AN: 5136

South Asian (SAS) AF: 0.383 AC: 1848 AN: 4824

European-Finnish (FIN) AF: 0.548 AC: 5791 AN: 10576

Middle Eastern (MID) AF: 0.438 AC: 128 AN: 292

European-Non Finnish (NFE) AF: 0.487 AC: 33080 AN: 67986

Other (OTH) AF: 0.461 AC: 974 AN: 2114

Alfa AF: 0.331 Hom.: 924

Bravo AF: 0.428

Asia WGS AF: 0.456 AC: 1580 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Bifunctional peroxisomal enzyme deficiency (2)
-	-	2	Perrault syndrome 1 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.7
DANN	Benign	0.55
PhyloP100		0.068
PromoterAI		0.058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs26180; hg19: chr5-118788196; COSMIC: COSV56333370; COSMIC: COSV56333370;