rs201619500
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5BP4_StrongBS2
The NM_017777.4(MKS1):c.1388G>A(p.Arg463Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00261 in 1,614,132 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R463G) has been classified as Pathogenic.
Frequency
Consequence
NM_017777.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MKS1 | NM_017777.4 | c.1388G>A | p.Arg463Gln | missense_variant | 15/18 | ENST00000393119.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MKS1 | ENST00000393119.7 | c.1388G>A | p.Arg463Gln | missense_variant | 15/18 | 1 | NM_017777.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00229 AC: 348AN: 152134Hom.: 7 Cov.: 32
GnomAD3 exomes AF: 0.00220 AC: 548AN: 249540Hom.: 3 AF XY: 0.00222 AC XY: 301AN XY: 135396
GnomAD4 exome AF: 0.00264 AC: 3863AN: 1461880Hom.: 11 Cov.: 31 AF XY: 0.00260 AC XY: 1893AN XY: 727238
GnomAD4 genome ? AF: 0.00229 AC: 348AN: 152252Hom.: 7 Cov.: 32 AF XY: 0.00230 AC XY: 171AN XY: 74448
ClinVar
Submissions by phenotype
not provided Benign:6
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | MKS1: BP4, BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 01, 2020 | This variant is associated with the following publications: (PMID: 27353947, 31456290) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Mar 09, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 14, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2023 | Variant summary: MKS1 c.1388G>A (p.Arg463Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 249540 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 1.96 fold of the estimated maximal expected allele frequency for a pathogenic variant in MKS1 causing Meckel Syndrome Type 1 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1388G>A in individuals affected with Meckel Syndrome Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (likely pathogenic n=1, VUS n=1, likely benign/benign n=7). Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 22, 2017 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Meckel syndrome, type 1 Uncertain:1Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 07, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Bardet-Biedl syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Bardet-Biedl syndrome 13 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at