rs1553387094

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The ENST00000389048.8(ALK):​c.4343C>T​(p.Ser1448Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1448P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ALK
ENST00000389048.8 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.08
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_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22108862).
BP6
Variant 2-29193744-G-A is Benign according to our data. Variant chr2-29193744-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 470871.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ALKNM_004304.5 linkuse as main transcriptc.4343C>T p.Ser1448Phe missense_variant 29/29 ENST00000389048.8 NP_004295.2
ALKNM_001353765.2 linkuse as main transcriptc.1139C>T p.Ser380Phe missense_variant 10/10 NP_001340694.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ALKENST00000389048.8 linkuse as main transcriptc.4343C>T p.Ser1448Phe missense_variant 29/291 NM_004304.5 ENSP00000373700 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
36
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 13, 2023In 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: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 470871). This variant has not been reported in the literature in individuals affected with ALK-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1448 of the ALK protein (p.Ser1448Phe). -
Ovarian cancer Benign:1
Benign, criteria provided, single submitterclinical testingLaboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan UniversityJan 01, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.062
T;T;.
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.32
N
LIST_S2
Benign
0.75
T;T;T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.22
T;T;T
MetaSVM
Benign
-0.76
T
MutationAssessor
Benign
1.8
.;L;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-2.9
.;D;.
REVEL
Benign
0.076
Sift
Benign
0.057
.;T;.
Sift4G
Benign
0.43
.;T;T
Polyphen
0.66
.;P;.
Vest4
0.24, 0.26
MutPred
0.18
.;Loss of phosphorylation at S1448 (P = 0.0091);.;
MVP
0.70
MPC
0.31
ClinPred
0.85
D
GERP RS
4.5
Varity_R
0.090
gMVP
0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553387094; hg19: chr2-29416610; COSMIC: COSV105929815; COSMIC: COSV105929815; API