Genetic Variant NM_001013619.4:c.1027A>G (chr15-78533575-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001013619.4(HYKK):c.1027A>G(p.Lys343Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0855 in 1,614,076 control chromosomes in the GnomAD database, including 6,575 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.070 ( 507 hom., cov: 33)

Exomes 𝑓: 0.087 ( 6068 hom. )

Consequence

HYKK
NM_001013619.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.84

Publications

38 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014449358).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0972 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYKK	NM_001013619.4 link	c.1027A>G	p.Lys343Glu	missense_variant	Exon 5 of 5	ENST00000388988.9	NP_001013641.2	A2RU49-1
HYKK	NM_001083612.2 link	c.662-3725A>G		intron_variant	Intron 4 of 4		NP_001077081.1	A2RU49-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HYKK	ENST00000388988.9 link	c.1027A>G	p.Lys343Glu	missense_variant	Exon 5 of 5	5	NM_001013619.4	ENSP00000373640.4	A2RU49-1
HYKK	ENST00000569878.5 link	c.1027A>G	p.Lys343Glu	missense_variant	Exon 4 of 4	5		ENSP00000455459.1	A2RU49-1
HYKK	ENST00000408962.6 link	c.662-3725A>G		intron_variant	Intron 4 of 4	5		ENSP00000386197.2	A2RU49-3
HYKK	ENST00000563233.2 link	c.662-3725A>G		intron_variant	Intron 3 of 3	2		ENSP00000454850.1	A2RU49-3

Frequencies

GnomAD3 genomes

AF:

0.0696

AC:

10593

AN:

152166

Hom.:

508

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0181

Gnomad AMI

AF:

0.121

Gnomad AMR

AF:

0.0891

Gnomad ASJ

AF:

0.144

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0567

Gnomad FIN

AF:

0.0562

Gnomad MID

AF:

0.187

Gnomad NFE

AF:

0.0991

Gnomad OTH

AF:

0.0932

GnomAD2 exomes

AF:

0.0753

AC:

18779

AN:

249552

AF XY:

0.0786

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.0608

Gnomad ASJ exome

AF:

0.147

Gnomad EAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.0576

Gnomad NFE exome

AF:

0.0993

Gnomad OTH exome

AF:

0.103

GnomAD4 exome

AF:

0.0871

AC:

127353

AN:

1461792

Hom.:

6068

Cov.:

AF XY:

0.0868

AC XY:

63101

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0158

AC:

529

AN:

33480

American (AMR)

AF:

0.0646

AC:

2887

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3756

AN:

26134

East Asian (EAS)

AF:

0.000327

AC:

AN:

39698

South Asian (SAS)

AF:

0.0615

AC:

5301

AN:

86254

European-Finnish (FIN)

AF:

0.0616

AC:

3289

AN:

53418

Middle Eastern (MID)

AF:

0.140

AC:

810

AN:

5768

European-Non Finnish (NFE)

AF:

0.0949

AC:

105537

AN:

1111922

Other (OTH)

AF:

0.0866

AC:

5231

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

6399

12798

19197

25596

31995

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3758

7516

11274

15032

18790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0696

AC:

10592

AN:

152284

Hom.:

507

Cov.:

AF XY:

0.0673

AC XY:

5009

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0181

AC:

752

AN:

41560

American (AMR)

AF:

0.0890

AC:

1362

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

499

AN:

3468

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.0567

AC:

273

AN:

4816

European-Finnish (FIN)

AF:

0.0562

AC:

597

AN:

10614

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0992

AC:

6745

AN:

68024

Other (OTH)

AF:

0.0922

AC:

195

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

524

1048

1573

2097

2621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0907

Hom.:

2802

Bravo

AF:

0.0701

TwinsUK

AF:

0.101

AC:

376

ALSPAC

AF:

0.0963

AC:

371

ESP6500AA

AF:

0.0182

AC:

ESP6500EA

AF:

0.104

AC:

855

ExAC

AF:

0.0752

AC:

9090

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.107

EpiControl

AF:

0.111

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.73

T;.

MetaRNN

Benign

0.0014

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

1.8

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.068

Sift

Benign

0.15

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.0060

B;B

Vest4

0.092

MPC

0.21

ClinPred

0.026

GERP RS

5.8

Varity_R

0.28

gMVP

0.19

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over