NM_004304.5:c.3408C>T
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_004304.5(ALK):c.3408C>T(p.Ser1136Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00481 in 1,613,970 control chromosomes in the GnomAD database, including 323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_004304.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -21 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0258 AC: 3915AN: 151990Hom.: 154 Cov.: 32
GnomAD3 exomes AF: 0.00671 AC: 1687AN: 251328Hom.: 73 AF XY: 0.00458 AC XY: 622AN XY: 135848
GnomAD4 exome AF: 0.00263 AC: 3839AN: 1461862Hom.: 169 Cov.: 34 AF XY: 0.00216 AC XY: 1574AN XY: 727234
GnomAD4 genome AF: 0.0258 AC: 3918AN: 152108Hom.: 154 Cov.: 32 AF XY: 0.0254 AC XY: 1889AN XY: 74352
ClinVar
Submissions by phenotype
Neuroblastoma, susceptibility to, 3 Benign:4
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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not provided Benign:2
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Variant summary: The ALK c.3408C>T (p.Ser1136Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 1019/121152 control chromosomes (44 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.0932024 (968/10386). This frequency is about 223686 times the estimated maximal expected allele frequency of a pathogenic ALK variant (0.0000004), suggesting this is likely a common benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as Benign. -
not specified Benign:1
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
ALK-related disorder Benign:1
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary cancer-predisposing syndrome Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at