chr15-41504427-C-T

Variant names:

• chr15-41504427-C-T
• rs752801446
• NM_002344.6:c.2261G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_002344.6(LTK):​c.2261G>A​(p.Arg754His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: LTK NM_002344.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.774
• Publications: 5 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 39 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTK	NM_002344.6	MANE Select	c.2261G>A	p.Arg754His	missense	Exon 19 of 20	NP_002335.2
	LTK	NM_206961.4		c.2078G>A	p.Arg693His	missense	Exon 18 of 19	NP_996844.1	P29376-4
	LTK	NM_001135685.2		c.1871G>A	p.Arg624His	missense	Exon 17 of 18	NP_001129157.1	P29376-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTK	ENST00000263800.11	TSL:1 MANE Select	c.2261G>A	p.Arg754His	missense	Exon 19 of 20	ENSP00000263800.6	P29376-1
	LTK	ENST00000355166.9	TSL:1	c.2078G>A	p.Arg693His	missense	Exon 18 of 19	ENSP00000347293.5	P29376-4
	LTK	ENST00000561619.5	TSL:1	c.1355G>A	p.Arg452His	missense	Exon 13 of 14	ENSP00000458111.1	H3BVG6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251176 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461804 Hom.: 0 Cov.: 34 AF XY: 0.0000330 AC XY: 24 AN XY: 727206

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111980

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000602 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0086	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	-0.0025	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.77
PrimateAI	Benign	0.19	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.019	D
Sift4G	Benign	0.12	T
Polyphen		0.98	D
Vest4		0.49
MutPred		0.51		Gain of catalytic residue at M756 (P = 0.1153)
MVP		0.91
MPC		0.15
ClinPred		0.93	D
GERP RS		-0.85
Varity_R		0.21
gMVP		0.34
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs752801446; hg19: chr15-41796625; COSMIC: COSV105847089;