5-119452612-C-A

Variant names:

• chr5-119452612-C-A
• rs1561419761
• NM_000414.4:c.37C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001199291.3(HSD17B4):​c.-142C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HSD17B4 NM_001199291.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.692

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD17B4	NM_000414.4	c.37C>A	p.Leu13Met	missense_variant	Exon 1 of 24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7	c.37C>A	p.Leu13Met	missense_variant	Exon 1 of 24	2	NM_000414.4	ENSP00000424940.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 22, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.;.;D;.
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.6	M;.;M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.92	N;.;N;.;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0070	D;.;D;.;.
Sift4G	Uncertain	0.0070	D;.;D;.;.
Polyphen		1.0	D;.;.;D;.
Vest4		0.51
MutPred		0.64		Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);
MVP		0.78
ClinPred		0.72	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs1561419761; hg19: chr5-118788307;