rs1400239417
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2
The NM_004304.5(ALK):c.3595A>T(p.Met1199Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,710 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1199I) has been classified as Uncertain significance.
Frequency
Consequence
NM_004304.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.3595A>T | p.Met1199Leu | missense_variant | 23/29 | ENST00000389048.8 | |
ALK | NM_001353765.2 | c.391A>T | p.Met131Leu | missense_variant | 4/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.3595A>T | p.Met1199Leu | missense_variant | 23/29 | 1 | NM_004304.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251082Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135704
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461586Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727096
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1199 of the ALK protein (p.Met1199Leu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with medulloblastoma (PMID: 27179218). ClinVar contains an entry for this variant (Variation ID: 569205). 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 tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 09, 2019 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 07, 2022 | The p.M1199L variant (also known as c.3595A>T), located in coding exon 23 of the ALK gene, results from an A to T substitution at nucleotide position 3595. The methionine at codon 1199 is replaced by leucine, an amino acid with highly similar properties. This variant has been reported in the germline of an individual with medulloblastoma and was inherited from an unaffected parent (Trubicka J et al. Folia Neuropathol, 2016;54:23-30). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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