15-78515075-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001013619.4(HYKK):​c.445A>C​(p.Lys149Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,444,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K149E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HYKK NM_001013619.4 missense
• Clinical Significance: Not reported in ClinVar
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23943192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYKK	NM_001013619.4	c.445A>C	p.Lys149Gln	missense_variant	Exon 3 of 5	ENST00000388988.9	NP_001013641.2
HYKK	NM_001083612.2	c.445A>C	p.Lys149Gln	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>C	p.Lys149Gln	missense_variant	Exon 3 of 5	5	NM_001013619.4	ENSP00000373640.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000421 AC: 1 AN: 237314 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000313

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444946 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 718752

African (AFR) AF: 0.00 AC: 0 AN: 32610

American (AMR) AF: 0.0000231 AC: 1 AN: 43278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25826

East Asian (EAS) AF: 0.00 AC: 0 AN: 38194

South Asian (SAS) AF: 0.00 AC: 0 AN: 83776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102954

Other (OTH) AF: 0.00 AC: 0 AN: 59580

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.0022	T;.;T;T;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T;T;T;.;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;.;M;M
PhyloP100		6.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.81	N;N;N;N;N
REVEL	Benign	0.093
Sift	Benign	0.17	T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.018	B;B;.;B;B
Vest4		0.27
MutPred		0.51		Loss of MoRF binding (P = 0.0689);Loss of MoRF binding (P = 0.0689);Loss of MoRF binding (P = 0.0689);Loss of MoRF binding (P = 0.0689);Loss of MoRF binding (P = 0.0689);
MVP		0.38
MPC		0.30
ClinPred		0.39	T
GERP RS		4.7
Varity_R		0.22
gMVP		0.53

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;