Genetic Variant LTK:p.Arg727Pro (chr15-41504581-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_002344.6(LTK):c.2180G>C(p.Arg727Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,484 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R727H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LTK
NM_002344.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.586

Publications

5 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002344.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LTK	NM_002344.6	MANE Select	c.2180G>C	p.Arg727Pro	missense	Exon 18 of 20	NP_002335.2
LTK	NM_206961.4		c.1997G>C	p.Arg666Pro	missense	Exon 17 of 19	NP_996844.1	P29376-4
LTK	NM_001135685.2		c.1790G>C	p.Arg597Pro	missense	Exon 16 of 18	NP_001129157.1	P29376-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LTK	ENST00000263800.11	TSL:1 MANE Select	c.2180G>C	p.Arg727Pro	missense	Exon 18 of 20	ENSP00000263800.6	P29376-1
LTK	ENST00000355166.9	TSL:1	c.1997G>C	p.Arg666Pro	missense	Exon 17 of 19	ENSP00000347293.5	P29376-4
LTK	ENST00000561619.5	TSL:1	c.1274G>C	p.Arg425Pro	missense	Exon 12 of 14	ENSP00000458111.1	H3BVG6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250854

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461484

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111978

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.74

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.83

PhyloP100

0.59

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.35

Sift

Benign

0.095

Sift4G

Benign

0.18

Polyphen

0.97

Vest4

0.47

MutPred

0.56

Gain of catalytic residue at M722 (P = 0.0278)

MVP

0.73

MPC

0.22

ClinPred

0.92

GERP RS

-1.0

Varity_R

0.56

gMVP

0.67

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over