rs140928266
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_004304.5(ALK):c.1148A>T(p.Lys383Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. K383T) 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 -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.1148A>T | p.Lys383Met | missense_variant | 4/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.2075A>T | non_coding_transcript_exon_variant | 4/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.1148A>T | p.Lys383Met | missense_variant | 4/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.17A>T | p.Lys6Met | missense_variant | 3/28 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251122Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135732
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461822Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727204
GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74498
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change replaces lysine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 383 of the ALK protein (p.Lys383Met). This variant is present in population databases (rs140928266, 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: 538201). 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 | Baylor Genetics | Oct 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Oct 16, 2023 | The ALK c.1148A>T (p.Lys383Met) missense change has a maximum subpopulation frequency of 0.048% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with ALK-related neuroblastic tumor susceptibility. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at