15-78515075-A-G

Variant summary

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

The NM_001013619.4(HYKK):c.445A>G(p.Lys149Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HYKK NM_001013619.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27001566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HYKK	NM_001013619.4	c.445A>G	p.Lys149Glu	missense_variant	3/5	ENST00000388988.9
HYKK	NM_001083612.2	c.445A>G	p.Lys149Glu	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYKK	ENST00000388988.9	c.445A>G	p.Lys149Glu	missense_variant	3/5	5	NM_001013619.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

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

Feb 22, 2023

The c.445A>G (p.K149E) alteration is located in exon 3 (coding exon 2) of the HYKK gene. This alteration results from a A to G substitution at nucleotide position 445, causing the lysine (K) at amino acid position 149 to be replaced by a glutamic acid (E). 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	Benign	0.16
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0020	T;.;T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.085
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T;T;.;.
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.77	N;N;N;N;N
REVEL	Benign	0.094
Sift	Benign	0.14	T;D;D;T;D
Sift4G	Benign	0.19	T;T;T;T;T
Polyphen		0.018	B;B;.;B;B
Vest4		0.34
MutPred		0.51		Loss of MoRF binding (P = 0.0315);Loss of MoRF binding (P = 0.0315);Loss of MoRF binding (P = 0.0315);Loss of MoRF binding (P = 0.0315);Loss of MoRF binding (P = 0.0315);
MVP		0.29
MPC		0.32
ClinPred		0.90	D
GERP RS		4.7
Varity_R		0.23
gMVP		0.58

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: chr15-78807417;