rs727502817
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP5_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
Genomes: not found (cov: 30)
Consequence
MAF
NM_005360.5 missense
NM_005360.5 missense
Scores
5
9
2
Clinical Significance
Conservation
PhyloP100: 8.85
Genes affected
MAF (HGNC:6776): (MAF bZIP transcription factor) The protein encoded by this gene is a DNA-binding, leucine zipper-containing transcription factor that acts as a homodimer or as a heterodimer. Depending on the binding site and binding partner, the encoded protein can be a transcriptional activator or repressor. This protein plays a role in the regulation of several cellular processes, including embryonic lens fiber cell development, increased T-cell susceptibility to apoptosis, and chondrocyte terminal differentiation. Defects in this gene are a cause of juvenile-onset pulverulent cataract as well as congenital cerulean cataract 4 (CCA4). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2010]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a region_of_interest Disordered (size 27) in uniprot entity MAF_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) in NM_005360.5
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 16-79599697-G-C is Pathogenic according to our data. Variant chr16-79599697-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162518.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-79599697-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAF | NM_005360.5 | c.206C>G | p.Pro69Arg | missense_variant | 1/2 | ENST00000326043.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAF | ENST00000326043.5 | c.206C>G | p.Pro69Arg | missense_variant | 1/2 | 1 | NM_005360.5 | A2 | |
MAF | ENST00000569649.1 | c.206C>G | p.Pro69Arg | missense_variant | 1/2 | 5 | P4 | ||
MAF | ENST00000393350.1 | c.206C>G | p.Pro69Arg | missense_variant | 1/1 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome Cov.: 36
GnomAD4 exome
Cov.:
36
GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ayme-Gripp syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | May 07, 2015 | - - |
Pathogenic, no assertion criteria provided | not provided | Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2016 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
Sift
Uncertain
D;D;D
Sift4G
Benign
T;D;T
Polyphen
0.99, 0.98
.;D;D
Vest4
MutPred
Gain of solvent accessibility (P = 0.007);Gain of solvent accessibility (P = 0.007);Gain of solvent accessibility (P = 0.007);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at