rs113994091
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2
The NM_004304.5(ALK):c.3452C>T(p.Thr1151Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. T1151P) has been classified as Uncertain significance.
Frequency
Consequence
NM_004304.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.3452C>T | p.Thr1151Met | missense_variant, splice_region_variant | 22/29 | ENST00000389048.8 | |
ALK | NM_001353765.2 | c.248C>T | p.Thr83Met | missense_variant, splice_region_variant | 3/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.3452C>T | p.Thr1151Met | missense_variant, splice_region_variant | 22/29 | 1 | NM_004304.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251346Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135860
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461862Hom.: 0 Cov.: 34 AF XY: 0.0000248 AC XY: 18AN XY: 727230
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74268
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:1Benign:1Other:2
risk factor, no assertion criteria provided | literature only | OMIM | Oct 16, 2008 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1151 of the ALK protein (p.Thr1151Met). This variant is present in population databases (rs113994091, gnomAD 0.01%). This missense change has been observed in individual(s) with neuroblastoma (PMID: 18923525; Invitae). ClinVar contains an entry for this variant (Variation ID: 18086). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change does not substantially affect ALK function (PMID: 18923525, 23104988). In 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Neuroblastoma Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: ERK activation, foci stimulation, and auto-phosphorylation similar to wildtype (George et al., 2008; Chand et al., 2013); Identified in an individual with neuroblastoma and another with pediatric leukemia (George et al., 2008; Waanders et al., 2017); This variant is associated with the following publications: (PMID: 18923525, 22072639, 21838707, 27733777, 27009859, 23104988) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2022 | The p.T1151M variant (also known as c.3452C>T), located in coding exon 22 of the ALK gene, results from a C to T substitution at nucleotide position 3452. The threonine at codon 1151 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in the germline of an individual with neuroblastoma (George RE et al. Nature. 2008 Oct;455:975-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at