rs727502817
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP2PP5_Moderate
The NM_005360.5(MAF):c.206C>G(p.Pro69Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_005360.5 missense
Scores
Clinical Significance
Conservation
Publications
- Ayme-Gripp syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
- cataract 21 multiple typesInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
- cataract - microcornea syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- cerulean cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- pulverulent cataractInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fine-Lubinsky syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome Cov.: 36
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Ayme-Gripp syndrome Pathogenic:2
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not provided Pathogenic:1
The P69R likely pathogenic variant has been previously reported as an assumed de novo variant identified in an individual with cataracts, blindness, sensorineural hearing loss, seizures, brachycephaly, facial dysmorphism, short stature, intellectual disability and autistic features (Gripp et al., 1996; Niceta et al., 2015). Functional and expression studies have shown P69R exhibits less activity than wild type and impairs phosphorylation of the MAF protein by altering a Proline residue adjacent to the phosphorylation site (Niceta et al., 2015). The P69R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with MAF-related disorders (Stenson et al., 2014). Therefore, the P69R variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at