15-78533374-G-A

Variant summary

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

The NM_001013619.4(HYKK):c.826G>A(p.Glu276Lys) variant causes a missense change involving the alteration of a 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: HYKK NM_001013619.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

HYKK (HGNC:34403): (hydroxylysine kinase) Enables hydroxylysine kinase activity. Predicted to be involved in lysine catabolic process. Predicted to be located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HYKK	NM_001013619.4	c.826G>A	p.Glu276Lys	missense_variant	5/5	ENST00000388988.9
HYKK	NM_001083612.2	c.662-3926G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYKK	ENST00000388988.9	c.826G>A	p.Glu276Lys	missense_variant	5/5	5	NM_001013619.4	P1
HYKK	ENST00000569878.5	c.826G>A	p.Glu276Lys	missense_variant	4/4	5		P1
HYKK	ENST00000408962.6	c.662-3926G>A		intron_variant		5
HYKK	ENST00000563233.2	c.662-3926G>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The c.826G>A (p.E276K) alteration is located in exon 5 (coding exon 4) of the HYKK gene. This alteration results from a G to A substitution at nucleotide position 826, causing the glutamic acid (E) at amino acid position 276 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.020	T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		0.44	B;B
Vest4		0.78
MutPred		0.74		Gain of methylation at E276 (P = 0.0037);Gain of methylation at E276 (P = 0.0037);
MVP		0.52
MPC		0.68
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.46
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-78825716;