rs1215186876

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The ENST00000389048.8(ALK):​c.4079G>T​(p.Arg1360Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1360Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ALK
ENST00000389048.8 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
ALK (HGNC:427): (ALK receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]
CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a domain Protein kinase (size 276) in uniprot entity ALK_HUMAN there are 29 pathogenic changes around while only 4 benign (88%) in ENST00000389048.8
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALKNM_004304.5 linkuse as main transcriptc.4079G>T p.Arg1360Leu missense_variant 28/29 ENST00000389048.8 NP_004295.2
ALKNM_001353765.2 linkuse as main transcriptc.875G>T p.Arg292Leu missense_variant 9/10 NP_001340694.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALKENST00000389048.8 linkuse as main transcriptc.4079G>T p.Arg1360Leu missense_variant 28/291 NM_004304.5 ENSP00000373700 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 29, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with ALK-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with leucine at codon 1360 of the ALK protein (p.Arg1360Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Benign
0.084
T;D;.
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.91
D;D;T
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.90
D;D;D
MetaSVM
Uncertain
0.42
D
MutationAssessor
Benign
1.0
.;L;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-6.6
.;D;.
REVEL
Pathogenic
0.84
Sift
Uncertain
0.012
.;D;.
Sift4G
Uncertain
0.016
.;D;D
Polyphen
1.0
.;D;.
Vest4
0.89, 0.91
MutPred
0.66
.;Loss of disorder (P = 0.0877);.;
MVP
0.96
MPC
0.79
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.87
gMVP
0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-29419721; API