15-78515075-A-G

Variant names:

• chr15-78515075-A-G
• rs751013035
• NM_001013619.4:c.445A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 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
• 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: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
HYKK	NM_001013619.4	c.445A>G	p.Lys149Glu	missense_variant	Exon 3 of 5	ENST00000388988.9	NP_001013641.2
HYKK	NM_001083612.2	c.445A>G	p.Lys149Glu	missense_variant	Exon 3 of 5		NP_001077081.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HYKK	ENST00000388988.9	c.445A>G	p.Lys149Glu	missense_variant	Exon 3 of 5	5	NM_001013619.4	ENSP00000373640.4

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

Feb 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		6.4
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

Other links and lift over

dbSNP: rs751013035; hg19: chr15-78807417;