rs1060500226
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_004304.5(ALK):c.3929C>T(p.Thr1310Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004304.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251360Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135838
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461106Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726928
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:2
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1310 of the ALK protein (p.Thr1310Ile). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ALK-related conditions. ClinVar contains an entry for this variant (Variation ID: 404377). 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. 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. -
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.T1310I variant (also known as c.3929C>T), located in coding exon 26 of the ALK gene, results from a C to T substitution at nucleotide position 3929. The threonine at codon 1310 is replaced by isoleucine, an amino acid with similar properties. 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