rs148001139
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_004304.5(ALK):c.2623G>A(p.Gly875Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,614,108 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. G875E) 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.2623G>A | p.Gly875Arg | missense_variant | 15/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.3550G>A | non_coding_transcript_exon_variant | 15/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.2623G>A | p.Gly875Arg | missense_variant | 15/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.1492G>A | p.Gly498Arg | missense_variant | 14/28 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152224Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251440Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135906
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727242
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152224Hom.: 0 Cov.: 34 AF XY: 0.0000403 AC XY: 3AN XY: 74364
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 26, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 875 of the ALK protein (p.Gly875Arg). This variant is present in population databases (rs148001139, gnomAD 0.01%). 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: 582569). 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 36315513); This variant is associated with the following publications: (PMID: 25714698, 25054154, 27287813, 36315513) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at