chr2-29225518-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_004304.5(ALK):c.3115G>A(p.Val1039Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000992 in 1,613,538 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. V1039A) 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 -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.3115G>A | p.Val1039Met | missense_variant | 19/29 | ENST00000389048.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.3115G>A | p.Val1039Met | missense_variant | 19/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.1984G>A | p.Val662Met | missense_variant | 18/28 | 5 | |||
ALK | ENST00000431873.6 | c.283G>A | p.Val95Met | missense_variant, NMD_transcript_variant | 3/14 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000109 AC: 27AN: 248440Hom.: 0 AF XY: 0.0000895 AC XY: 12AN XY: 134020
GnomAD4 exome AF: 0.000103 AC: 150AN: 1461230Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 76AN XY: 726800
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5AN XY: 74468
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 05, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1039 of the ALK protein (p.Val1039Met). This variant is present in population databases (rs200080181, gnomAD 0.02%). 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: 404367). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Familial isolated pituitary adenoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | May 20, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Present in cancer-free control individuals but not observed in melanoma cases (Pritchard et al., 2018); This variant is associated with the following publications: (PMID: 29641532) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at