rs751646311

Positions:

• chr5-119536458-C-A
• chr5-119536458-C-G
• chr5-119536458-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000414.4(HSD17B4):​c.2029C>A​(p.Gln677Lys) variant causes a missense 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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSD17B4 NM_000414.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23178557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD17B4	NM_000414.4	c.2029C>A	p.Gln677Lys	missense_variant	23/24	ENST00000510025.7	NP_000405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD17B4	ENST00000510025.7	c.2029C>A	p.Gln677Lys	missense_variant	23/24	2	NM_000414.4	ENSP00000424940	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.038	T;.;T;.;.;.;T;.;T;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.79	.;T;T;.;T;T;T;T;T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N;.;N;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.77	D;D;D;D;D;D;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.10	N;N;.;.;N;.;.;.;N;N;.
REVEL	Benign	0.050
Sift	Benign	0.58	T;T;.;.;T;.;.;.;T;T;.
Sift4G	Benign	1.0	T;T;.;.;T;.;.;.;T;T;.
Polyphen		0.0050	B;.;B;.;.;.;B;.;.;B;.
Vest4		0.14
MutPred		0.46		Loss of ubiquitination at K674 (P = 0.0258);.;Loss of ubiquitination at K674 (P = 0.0258);.;.;Loss of ubiquitination at K674 (P = 0.0258);.;.;.;.;.;
MVP		0.24
MPC		0.075
ClinPred		0.55	D
GERP RS		4.0
Varity_R		0.22
gMVP		0.38

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: rs751646311; hg19: chr5-118872153; COSMIC: COSV105846000;