rs1554062814

Variant names:

• chr5-119478922-G-A
• rs1554062814
• NM_000414.4:c.523G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-119478922-G-A
• chr5-119478922-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000414.4(HSD17B4):​c.523G>A​(p.Ala175Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: -0.256

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-119478922-G-A is Pathogenic according to our data. Variant chr5-119478922-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555994.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.334434). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4	c.523G>A	p.Ala175Thr	missense_variant	Exon 8 of 24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7	c.523G>A	p.Ala175Thr	missense_variant	Exon 8 of 24	2	NM_000414.4	ENSP00000424940.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461372 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726980

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bifunctional peroxisomal enzyme deficiency Pathogenic:1 Uncertain:1

Jan 05, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 04, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HSD17B4 c.523G>A (p.Ala175Thr) results in a non-conservative amino acid change located in the NAD(P)-binding Rossmann-fold domains (IPR036291) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251078 control chromosomes (gnomAD). c.523G>A has been reported in the literature in individuals affected with clinical features of D-Bifunctional Protein Deficiency (Matsukawa_2017, Matsuda_2020). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32042923, 28017249). ClinVar contains an entry for this variant (Variation ID: 555994). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0031	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.42	T;.;T;.;.;.;T;.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.43	N
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.65	N;.;N;.;.;.;.;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.95	N;N;.;.;N;.;.;.;N;.
REVEL	Uncertain	0.38
Sift	Benign	0.17	T;T;.;.;T;.;.;.;T;.
Sift4G	Benign	0.45	T;T;.;.;T;.;.;.;T;.
Polyphen		0.32	B;.;B;.;.;.;B;.;.;.
Vest4		0.47
MutPred		0.81		Gain of catalytic residue at A175 (P = 0.2065);.;Gain of catalytic residue at A175 (P = 0.2065);.;.;Gain of catalytic residue at A175 (P = 0.2065);.;.;.;.;
MVP		0.53
MPC		0.072
ClinPred		0.14	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554062814; hg19: chr5-118814617;