NM_017777.4:c.1411dupG
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_017777.4(MKS1):c.1411dupG(p.Glu471GlyfsTer120) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,612,106 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017777.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151990Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000648 AC: 16AN: 247054Hom.: 0 AF XY: 0.0000596 AC XY: 8AN XY: 134120
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1460116Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 726380
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151990Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74232
ClinVar
Submissions by phenotype
Meckel syndrome, type 1 Pathogenic:2
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Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Pathogenic:1
This sequence change results in a frameshift in the MKS1 gene (p.Glu471Glyfs*120). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the MKS1 protein and extend the protein by 30 additional amino acid residues. This variant is present in population databases (rs762668200, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with MKS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 435876). This variant results in an extension of the MKS1 protein. Other variant(s) that result in a similarly extended protein product (p.Thr485Argfs*107) have been determined to be pathogenic (PMID: 17185389, 17397051). This suggests that these extensions are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Bardet-Biedl syndrome 13 Pathogenic:1
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Bardet-Biedl syndrome 13;C3714506:Meckel syndrome, type 1;C4310705:Joubert syndrome 28 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at