rs111671384

Variant names:

• chr5-119542000-A-G
• rs111671384
• NM_000414.4:c.*6A>G

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.*6A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,570,708 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (18 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (14 hom.)
• Consequence: HSD17B4 NM_000414.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.31
• Publications: 0 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=-0.69).
• BP6: Variant 5-119542000-A-G is Benign according to our data. Variant chr5-119542000-A-G is described in ClinVar as Benign. ClinVar VariationId is 226663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00725 (1104/152300) while in subpopulation AFR AF = 0.0254 (1054/41564). AF 95% confidence interval is 0.0241. There are 18 homozygotes in GnomAd4. There are 548 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.*6A>G		3_prime_UTR	Exon 24 of 24	NP_000405.1
	HSD17B4	NR_164653.1		n.2314A>G		non_coding_transcript_exon	Exon 24 of 24
	HSD17B4	NR_164654.1		n.2582A>G		non_coding_transcript_exon	Exon 25 of 25

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD17B4	ENST00000510025.7	TSL:2 MANE Select	c.*6A>G		3_prime_UTR	Exon 24 of 24	ENSP00000424940.3
	HSD17B4	ENST00000509514.6	TSL:1	c.*6A>G		3_prime_UTR	Exon 24 of 24	ENSP00000426272.2
	HSD17B4	ENST00000645099.1		c.*6A>G		splice_region	Exon 20 of 20	ENSP00000496091.1

Frequencies

GnomAD3 genomes AF: 0.00715 AC: 1088 AN: 152182 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00189 AC: 474 AN: 250926 AF XY: 0.00127

Gnomad AFR exome AF: 0.0260

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000742 AC: 1052 AN: 1418408 Hom.: 14 Cov.: 24 AF XY: 0.000641 AC XY: 454 AN XY: 708422

African (AFR) AF: 0.0257 AC: 826 AN: 32136

American (AMR) AF: 0.00157 AC: 70 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25818

East Asian (EAS) AF: 0.00 AC: 0 AN: 39434

South Asian (SAS) AF: 0.0000704 AC: 6 AN: 85284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00159 AC: 9 AN: 5678

European-Non Finnish (NFE) AF: 0.0000252 AC: 27 AN: 1073228

Other (OTH) AF: 0.00194 AC: 114 AN: 58904

GnomAD4 genome AF: 0.00725 AC: 1104 AN: 152300 Hom.: 18 Cov.: 32 AF XY: 0.00736 AC XY: 548 AN XY: 74472

African (AFR) AF: 0.0254 AC: 1054 AN: 41564

American (AMR) AF: 0.00196 AC: 30 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00527 Hom.: 6

Bravo AF: 0.00816

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Bifunctional peroxisomal enzyme deficiency (2)
-	-	1	not specified (1)
-	-	1	Perrault syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.7
DANN	Benign	0.81
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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: rs111671384; hg19: chr5-118877695;