rs774127733
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_004304.5(ALK):āc.1154G>Cā(p.Gly385Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000434 in 1,613,944 control chromosomes in the GnomAD database, including 1 homozygotes. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G385D) has been classified as Uncertain significance.
Frequency
Consequence
NM_004304.5 missense, splice_region
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.1154G>C | p.Gly385Ala | missense_variant, splice_region_variant | 4/29 | ENST00000389048.8 | |
ALK | XR_001738688.3 | n.2081G>C | splice_region_variant, non_coding_transcript_exon_variant | 4/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALK | ENST00000389048.8 | c.1154G>C | p.Gly385Ala | missense_variant, splice_region_variant | 4/29 | 1 | NM_004304.5 | P1 | |
ALK | ENST00000618119.4 | c.23G>C | p.Gly8Ala | missense_variant, splice_region_variant | 3/28 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250952Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135646
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461788Hom.: 1 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727188
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 05, 2023 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. ClinVar contains an entry for this variant (Variation ID: 404317). This variant has not been reported in the literature in individuals affected with ALK-related conditions. This variant is present in population databases (rs774127733, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 385 of the ALK protein (p.Gly385Ala). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at