rs745499366
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_004304.5(ALK):c.2257C>T(p.Arg753Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R753G) 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 -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALK | NM_004304.5 | c.2257C>T | p.Arg753Trp | missense_variant | 13/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.3184C>T | non_coding_transcript_exon_variant | 13/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.2257C>T | p.Arg753Trp | missense_variant | 13/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.1126C>T | p.Arg376Trp | missense_variant | 12/28 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 152140Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251050Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135716
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461648Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727136
GnomAD4 genome ? Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74314
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 02, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2023 | 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. ClinVar contains an entry for this variant (Variation ID: 538196). This variant has not been reported in the literature in individuals affected with ALK-related conditions. This variant is present in population databases (rs745499366, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 753 of the ALK protein (p.Arg753Trp). - |
ALK-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 19, 2022 | The ALK c.2257C>T variant is predicted to result in the amino acid substitution p.Arg753Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-29462644-G-A) and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/538196/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at