NM_001013619.4:c.242A>G

Variant names:

• chr15-78513330-A-G
• NM_001013619.4:c.242A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001013619.4(HYKK):​c.242A>G​(p.Gln81Arg) variant causes a missense change. 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: 31)
• Consequence: HYKK NM_001013619.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.96
• Publications: 0 publications found

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]

HYKK Gene-Disease associations (from GenCC):

• inborn disorder of lysine and hydroxylysine metabolism

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYKK	NM_001013619.4	c.242A>G	p.Gln81Arg	missense_variant	Exon 2 of 5	ENST00000388988.9	NP_001013641.2
HYKK	NM_001083612.2	c.242A>G	p.Gln81Arg	missense_variant	Exon 2 of 5		NP_001077081.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HYKK	ENST00000388988.9	c.242A>G	p.Gln81Arg	missense_variant	Exon 2 of 5	5	NM_001013619.4	ENSP00000373640.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.242A>G (p.Q81R) alteration is located in exon 2 (coding exon 1) of the HYKK gene. This alteration results from a A to G substitution at nucleotide position 242, causing the glutamine (Q) at amino acid position 81 to be replaced by an arginine (R). 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	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.095	T;.;T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;T;T;.;.
M_CAP	Benign	0.082	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	3.5	H;H;.;H;H
PhyloP100		6.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.94	P;D;.;P;D
Vest4		0.86
MutPred		0.81		Gain of methylation at Q81 (P = 0.151);Gain of methylation at Q81 (P = 0.151);Gain of methylation at Q81 (P = 0.151);Gain of methylation at Q81 (P = 0.151);Gain of methylation at Q81 (P = 0.151);
MVP		0.64
MPC		0.67
ClinPred		0.99	D
GERP RS		4.7
PromoterAI		0.0088	Neutral
Varity_R		0.77
gMVP		0.91

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

Other links and lift over

hg19: chr15-78805672;