Genetic Variant HYKK:p.Tyr145His (chr15-78515063-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001013619.4(HYKK):c.433T>C(p.Tyr145His) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,448,126 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HYKK
NM_001013619.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.23

Publications

0 publications found

Variant links:

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

HYKK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYKK	NM_001013619.4 link	c.433T>C	p.Tyr145His	missense_variant	Exon 3 of 5	ENST00000388988.9	NP_001013641.2	A2RU49-1
HYKK	NM_001083612.2 link	c.433T>C	p.Tyr145His	missense_variant	Exon 3 of 5		NP_001077081.1	A2RU49-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HYKK	ENST00000388988.9 link	c.433T>C	p.Tyr145His	missense_variant	Exon 3 of 5	5	NM_001013619.4	ENSP00000373640.4		A2RU49-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1448126

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720364

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32816

American (AMR)

AF:

0.00

AC:

AN:

43650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25902

East Asian (EAS)

AF:

0.00

AC:

AN:

38454

South Asian (SAS)

AF:

0.00

AC:

AN:

84208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53114

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1104566

Other (OTH)

AF:

0.00

AC:

AN:

59712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.433T>C (p.Y145H) alteration is located in exon 3 (coding exon 2) of the HYKK gene. This alteration results from a T to C substitution at nucleotide position 433, causing the tyrosine (Y) at amino acid position 145 to be replaced by a histidine (H). 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

0.22

BayesDel_addAF

Benign

-0.011

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.037

T;.;T;T;.

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D;.;.

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.78

D;D;D;D;D

MetaSVM

Benign

-0.65

MutationAssessor

Pathogenic

3.3

M;M;.;M;M

PhyloP100

5.2

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.5

D;D;D;D;D

REVEL

Benign

0.29

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Uncertain

0.027

D;D;D;D;D

Polyphen

0.91

P;D;.;P;D

Vest4

0.63

MutPred

0.66

Loss of catalytic residue at Y145 (P = 0.05);Loss of catalytic residue at Y145 (P = 0.05);Loss of catalytic residue at Y145 (P = 0.05);Loss of catalytic residue at Y145 (P = 0.05);Loss of catalytic residue at Y145 (P = 0.05);

MVP

0.45

MPC

0.73

ClinPred

0.94

GERP RS

4.7

Varity_R

0.72

gMVP

0.72

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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15-78515063-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over