rs1553394197

Variant names:

• chr2-29222350-A-T
• rs1553394197
• NM_004304.5:c.3509T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_004304.5(ALK):​c.3509T>A​(p.Ile1170Asn) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31
• Publications: 1 publications found

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]

ALK Gene-Disease associations (from GenCC):

• neuroblastoma, susceptibility to, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_004304.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5	c.3509T>A	p.Ile1170Asn	missense_variant	Exon 22 of 29	ENST00000389048.8	NP_004295.2
ALK	NM_001353765.2	c.305T>A	p.Ile102Asn	missense_variant	Exon 3 of 10		NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.3509T>A	p.Ile1170Asn	missense_variant	Exon 22 of 29	1	NM_004304.5	ENSP00000373700.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Uncertain:1

Jul 17, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change is located within the functionally conserved tyrosine kinase domain of the ALK protein, where a significant number of previously reported somatic and germline ALK missense mutations have been reported (PMID: 18724359, 21972109, 18923524). One experimental study has shown that this variant accelerated the autophosphorylation of the ALK tyrosine kinase domain in vitro, which is necessary for its activation (PMID: 25517749). In summary, this variant has been shown to disrupt protein function in vitro. However, further genetic data is necessary at this point to unequivocally classify this variant. Therefore, it has been classified as a Variant of Uncertain Significance. This has not been reported in the literature in the germline of individuals with an ALK-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with asparagine at codon 1170 of the ALK protein (p.Ile1170Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.098	T;D;.;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.7	.;L;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.9	.;D;.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	.;D;.;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.93, 0.94
MutPred		0.84		.;Loss of stability (P = 0.029);.;.;
MVP		0.93
MPC		0.95
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.83
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs1553394197; hg19: chr2-29445216; COSMIC: COSV66589132;