Genetic Variant NM_002344.6:c.1603G>A (chr15-41505944-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002344.6(LTK):c.1603G>A(p.Asp535Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0256 in 1,613,806 control chromosomes in the GnomAD database, including 647 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 0.019 ( 50 hom., cov: 33)

Exomes 𝑓: 0.026 ( 597 hom. )

Consequence

LTK
NM_002344.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.94

Publications

20 publications found

Variant links:

Genes affected

LTK (HGNC:6721): (leukocyte receptor tyrosine kinase) The protein encoded by this gene is a member of the ros/insulin receptor family of tyrosine kinases. Tyrosine-specific phosphorylation of proteins is a key to the control of diverse pathways leading to cell growth and differentiation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

LTK 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=0.005242139).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0189 (2879/152280) while in subpopulation SAS AF = 0.0356 (172/4830). AF 95% confidence interval is 0.0313. There are 50 homozygotes in GnomAd4. There are 1383 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2879 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTK	NM_002344.6 link	c.1603G>A	p.Asp535Asn	missense_variant	Exon 12 of 20	ENST00000263800.11	NP_002335.2	P29376-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTK	ENST00000263800.11 link	c.1603G>A	p.Asp535Asn	missense_variant	Exon 12 of 20	1	NM_002344.6	ENSP00000263800.6		P29376-1

Frequencies

GnomAD3 genomes

AF:

0.0189

AC:

2883

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00531

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.0378

Gnomad EAS

AF:

0.00578

Gnomad SAS

AF:

0.0360

Gnomad FIN

AF:

0.0108

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0278

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.0222

AC:

5581

AN:

251258

AF XY:

0.0236

show subpopulations

Gnomad AFR exome

AF:

0.00375

Gnomad AMR exome

AF:

0.00984

Gnomad ASJ exome

AF:

0.0411

Gnomad EAS exome

AF:

0.00729

Gnomad FIN exome

AF:

0.0109

Gnomad NFE exome

AF:

0.0284

Gnomad OTH exome

AF:

0.0225

GnomAD4 exome

AF:

0.0263

AC:

38489

AN:

1461526

Hom.:

597

Cov.:

AF XY:

0.0267

AC XY:

19406

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.00397

AC:

133

AN:

33478

American (AMR)

AF:

0.0102

AC:

455

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.0431

AC:

1127

AN:

26122

East Asian (EAS)

AF:

0.00355

AC:

141

AN:

39696

South Asian (SAS)

AF:

0.0337

AC:

2908

AN:

86226

European-Finnish (FIN)

AF:

0.0119

AC:

635

AN:

53380

Middle Eastern (MID)

AF:

0.0302

AC:

174

AN:

5768

European-Non Finnish (NFE)

AF:

0.0284

AC:

31562

AN:

1111762

Other (OTH)

AF:

0.0224

AC:

1354

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1747

3493

5240

6986

8733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1198

2396

3594

4792

5990

<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:

0.0189

AC:

2879

AN:

152280

Hom.:

Cov.:

AF XY:

0.0186

AC XY:

1383

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00529

AC:

220

AN:

41552

American (AMR)

AF:

0.0171

AC:

261

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0378

AC:

131

AN:

3470

East Asian (EAS)

AF:

0.00580

AC:

AN:

5176

South Asian (SAS)

AF:

0.0356

AC:

172

AN:

4830

European-Finnish (FIN)

AF:

0.0108

AC:

115

AN:

10618

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0278

AC:

1891

AN:

68016

Other (OTH)

AF:

0.0185

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

147

293

440

586

733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0236

Hom.:

Bravo

AF:

0.0181

TwinsUK

AF:

0.0297

AC:

110

ALSPAC

AF:

0.0270

AC:

104

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.0295

AC:

254

ExAC

AF:

0.0228

AC:

2770

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.0261

EpiControl

AF:

0.0274

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

.;T;D

Eigen

Benign

0.095

Eigen_PC

Benign

0.076

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.87

D;D;D

MetaRNN

Benign

0.0052

T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

0.86

.;L;.

PhyloP100

3.9

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Benign

0.29

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.051

T;D;D

Polyphen

0.83

P;P;.

Vest4

0.16

MPC

0.12

ClinPred

0.056

GERP RS

0.83

Varity_R

0.44

gMVP

0.13

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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