rs1057519697
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_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. F1174V) has been classified as Pathogenic.
Frequency
Consequence
NM_004304.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.3521T>G | p.Phe1174Cys | missense_variant | 23/29 | ENST00000389048.8 | NP_004295.2 | |
ALK | NM_001353765.2 | c.317T>G | p.Phe106Cys | missense_variant | 4/10 | NP_001340694.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.3521T>G | p.Phe1174Cys | missense_variant | 23/29 | 1 | NM_004304.5 | ENSP00000373700.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at