5-119452631-C-T

Position:

• chr5-119452631-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000414.4(HSD17B4):​c.56C>T​(p.Ala19Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A19G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HSD17B4 NM_000414.4 missense, splice_region
• Scores: Splicing: ADA: 0.0008776
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.40

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000414.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40459222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD17B4	NM_000414.4	c.56C>T	p.Ala19Val	missense_variant, splice_region_variant	1/24	ENST00000510025.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD17B4	ENST00000510025.7	c.56C>T	p.Ala19Val	missense_variant, splice_region_variant	1/24	2	NM_000414.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.;.;D;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.61	D
LIST_S2	Pathogenic	0.98	.;D;T;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.2	L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.4	N;.;N;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.043	D;.;T;.;.
Sift4G	Uncertain	0.047	D;.;T;.;.
Polyphen		0.32	B;.;.;B;.
Vest4		0.22
MutPred		0.70		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.75
ClinPred		0.57	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00088
dbscSNV1_RF	Benign	0.054
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.87		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs148363262; hg19: chr5-118788326; COSMIC: COSV99819847; COSMIC: COSV99819847;