NM_000414.4:c.1767+57C>T

Variant names:

• chr5-119527276-C-T
• rs2636961
• NM_000414.4:c.1767+57C>T

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.1767+57C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 974,272 control chromosomes in the GnomAD database, including 176,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30167 hom., cov: 31)
  • Exomes 𝑓: 0.59 (146638 hom.)
• Consequence: HSD17B4 NM_000414.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.742
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 5-119527276-C-T is Benign according to our data. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-119527276-C-T is described in CliVar as Benign. Clinvar id is 1185150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4	c.1767+57C>T		intron_variant	Intron 20 of 23	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7	c.1767+57C>T		intron_variant	Intron 20 of 23	2	NM_000414.4	ENSP00000424940.3

Frequencies

GnomAD3 genomes AF: 0.625 AC: 94681 AN: 151602 Hom.: 30138 Cov.: 31

Gnomad AFR AF: 0.695

Gnomad AMI AF: 0.716

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.573

Gnomad FIN AF: 0.634

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.564

Gnomad OTH AF: 0.617

GnomAD4 exome AF: 0.586 AC: 481715 AN: 822552 Hom.: 146638 AF XY: 0.582 AC XY: 252534 AN XY: 434142

African (AFR) AF: 0.693 AC: 14509 AN: 20942

American (AMR) AF: 0.687 AC: 29542 AN: 43010

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 13852 AN: 21912

East Asian (EAS) AF: 0.936 AC: 34037 AN: 36378

South Asian (SAS) AF: 0.539 AC: 38797 AN: 71984

European-Finnish (FIN) AF: 0.643 AC: 33863 AN: 52654

Middle Eastern (MID) AF: 0.565 AC: 2178 AN: 3852

European-Non Finnish (NFE) AF: 0.548 AC: 291801 AN: 532760

Other (OTH) AF: 0.592 AC: 23136 AN: 39060

GnomAD4 genome AF: 0.625 AC: 94763 AN: 151720 Hom.: 30167 Cov.: 31 AF XY: 0.629 AC XY: 46627 AN XY: 74128

African (AFR) AF: 0.695 AC: 28794 AN: 41412

American (AMR) AF: 0.608 AC: 9260 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 2187 AN: 3470

East Asian (EAS) AF: 0.923 AC: 4781 AN: 5180

South Asian (SAS) AF: 0.573 AC: 2763 AN: 4818

European-Finnish (FIN) AF: 0.634 AC: 6663 AN: 10506

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.564 AC: 38210 AN: 67802

Other (OTH) AF: 0.613 AC: 1292 AN: 2108

Alfa AF: 0.598 Hom.: 40090

Bravo AF: 0.632

Asia WGS AF: 0.713 AC: 2463 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Perrault syndrome 1 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.23
DANN	Benign	0.25
PhyloP100		-0.74
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: rs2636961; hg19: chr5-118862971; COSMIC: COSV56333355; COSMIC: COSV56333355;