rs754971913
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_004304.5(ALK):c.1705G>A(p.Val569Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. V569A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004304.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.1705G>A | p.Val569Met | missense_variant | 9/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.2632G>A | non_coding_transcript_exon_variant | 9/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.1705G>A | p.Val569Met | missense_variant | 9/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.574G>A | p.Val192Met | missense_variant | 8/28 | 5 | |||
ALK | ENST00000498037.1 | n.260G>A | non_coding_transcript_exon_variant | 3/5 | 4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 12, 2020 | In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is present in population databases (rs754971913, ExAC 0.006%) but has not been reported in the literature in individuals with an ALK-related disease. This sequence change replaces valine with methionine at codon 569 of the ALK protein (p.Val569Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at