NM_001163435.3:c.1220+1G>A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001163435.3(TBCK):c.1220+1G>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000675 in 1,334,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001163435.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TBCK | NM_001163435.3 | c.1220+1G>A | splice_donor_variant, intron_variant | Intron 13 of 25 | ENST00000394708.7 | NP_001156907.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 151738Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.0000104 AC: 2AN: 191990Hom.: 0 AF XY: 0.0000190 AC XY: 2AN XY: 105442
GnomAD4 exome AF: 0.00000675 AC: 9AN: 1334126Hom.: 0 Cov.: 23 AF XY: 0.0000106 AC XY: 7AN XY: 663090
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 151738Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74092
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 Pathogenic:1
Variant summary: TBCK c.1220+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of TBCK function. The variant allele was found at a frequency of 6.1e-06 in 1485864 control chromosomes. To our knowledge, no occurrence of c.1220+1G>A in individuals affected with Hypotonia, Infantile, With Psychomotor Retardation And Characteristic Facies 3 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 446005). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at