rs372612147
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_004304.5(ALK):c.4375G>T(p.Ala1459Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000379 in 1,608,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. A1459V) has been classified as Uncertain significance.
Frequency
Consequence
NM_004304.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.4375G>T | p.Ala1459Ser | missense_variant | 29/29 | ENST00000389048.8 | |
ALK | NM_001353765.2 | c.1171G>T | p.Ala391Ser | missense_variant | 10/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.4375G>T | p.Ala1459Ser | missense_variant | 29/29 | 1 | NM_004304.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000243 AC: 37AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000522 AC: 13AN: 249224Hom.: 0 AF XY: 0.0000446 AC XY: 6AN XY: 134676
GnomAD4 exome AF: 0.0000165 AC: 24AN: 1456618Hom.: 0 Cov.: 36 AF XY: 0.0000152 AC XY: 11AN XY: 723840
GnomAD4 genome ? AF: 0.000243 AC: 37AN: 152320Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74476
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:1Benign:1
Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1459 of the ALK protein (p.Ala1459Ser). This variant is present in population databases (rs372612147, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. 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: 335689). 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 14, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at