rs1057519697

Positions:

• chr2-29220830-A-C
• chr2-29220830-A-G
• chr2-29220830-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_004304.5(ALK):​c.3521T>G​(p.Phe1174Cys) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1174I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.31

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_004304.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-29220831-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 217850.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant 2-29220830-A-C is Pathogenic according to our data. Variant chr2-29220830-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375887.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALK	NM_004304.5	c.3521T>G	p.Phe1174Cys	missense_variant	23/29	ENST00000389048.8
ALK	NM_001353765.2	c.317T>G	p.Phe106Cys	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALK	ENST00000389048.8	c.3521T>G	p.Phe1174Cys	missense_variant	23/29	1	NM_004304.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neuroblastoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

ALK-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2023

The ALK c.3521T>G variant is predicted to result in the amino acid substitution p.Phe1174Cys. This variant has been reported in somatic context in neuroblastoma tumors (Chang et al. 2015. PubMed ID: 26619011; Janoueix-Lerosey et al 2008. PubMed ID: 18923523). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Other variants at this codon p.Phe1174Val/Leu/Ile/Gln have been reported in somatic context in neuroblastoma and other tumor types and have been shown to be gain-of-function mutations (Chang et al. 2015. PubMed ID: 26619011; Janoueix-Lerosey et al. 2008. PubMed ID: 18923523; Bresler et al. 2011. PubMed ID: 22072639; Schönherr et al 2011. PubMed ID: 21838707). An alternate variant at this codon p.Phe1174Val has been reported as germline de novo mutation in a neonate with IUGR, hypotonia, gastroesophageal reflux, tracheobronchomalacia, calcified adrenal masses on thoracoabdominal CT scan at 3 weeks of age, patent foramen ovale with prolonged QT, bilateral hernia, abdominal distention, difficulty in swallowing, and abnormal shape of the brainstem with multifocal neuroblastoma of neonatal onset (de Pontual et al. 2011. PubMed ID: 21972109). This variant p.Phe1174Cys was observed as germline de novo mutation in neonate with IUGR, seizures, respiratory insufficiency, joint contractures, patent foramen ovale, patent ductus arteriosus and metastatic neuroblastoma (Internal data, PreventionGenetics). However, this gene-disease association has not been definitively established. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	0.40	.;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.9	.;D;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	.;D;.
Vest4		0.92, 0.92
MutPred		0.84		.;Gain of methylation at K1173 (P = 0.0326);.;
MVP		0.98
MPC		0.85
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.77

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

Other links and lift over

dbSNP: rs1057519697; hg19: chr2-29443696; COSMIC: COSV66560921; COSMIC: COSV66560921;