rs531490912
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_004304.5(ALK):c.4193C>T(p.Pro1398Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,614,104 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. P1398R) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.4193C>T | p.Pro1398Leu | missense_variant | 29/29 | ENST00000389048.8 | |
ALK | NM_001353765.2 | c.989C>T | p.Pro330Leu | missense_variant | 10/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.4193C>T | p.Pro1398Leu | missense_variant | 29/29 | 1 | NM_004304.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000559 AC: 14AN: 250424Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135658
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461828Hom.: 0 Cov.: 36 AF XY: 0.0000330 AC XY: 24AN XY: 727218
GnomAD4 genome ? AF: 0.000125 AC: 19AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74458
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 28, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1398 of the ALK protein (p.Pro1398Leu). This variant is present in population databases (rs531490912, gnomAD 0.05%), 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: 470866). 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 | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or kidney cancer (PMID: 29684080); This variant is associated with the following publications: (PMID: 29684080) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at