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

Genomes: not found (cov: 30)

Consequence

MAF
NM_005360.5 missense

Scores

6
10
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 8.85

Publications

6 publications found
Variant links:
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]
MAF Gene-Disease associations (from GenCC):
  • Ayme-Gripp syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • cataract 21 multiple types
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
  • cataract - microcornea syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • cerulean cataract
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • pulverulent cataract
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Fine-Lubinsky syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1
In a region_of_interest Disordered (size 27) in uniprot entity MAF_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_005360.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 1.1779 (below the threshold of 3.09). Trascript score misZ: -0.24854 (below the threshold of 3.09). GenCC associations: The gene is linked to cerulean cataract, Fine-Lubinsky syndrome, cataract 21 multiple types, Ayme-Gripp syndrome, pulverulent cataract, cataract - microcornea syndrome.
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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAFNM_005360.5 linkc.206C>G p.Pro69Arg missense_variant Exon 1 of 2 ENST00000326043.5 NP_005351.2 O75444-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAFENST00000326043.5 linkc.206C>G p.Pro69Arg missense_variant Exon 1 of 2 1 NM_005360.5 ENSP00000327048.4 O75444-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
36
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
May 07, 2015
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

-
Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:not provided

- -

not provided Pathogenic:1
Sep 22, 2016
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.76
.;.;D
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Pathogenic
0.97
D
MetaRNN
Uncertain
0.67
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Benign
1.4
.;L;L
PhyloP100
8.8
PrimateAI
Pathogenic
0.95
D
PROVEAN
Uncertain
-3.8
D;D;D
REVEL
Pathogenic
0.88
Sift
Uncertain
0.0010
D;D;D
Sift4G
Benign
0.067
T;D;T
Polyphen
0.99, 0.98
.;D;D
Vest4
0.72
MutPred
0.21
Gain of solvent accessibility (P = 0.007);Gain of solvent accessibility (P = 0.007);Gain of solvent accessibility (P = 0.007);
MVP
0.99
ClinPred
0.99
D
GERP RS
3.1
PromoterAI
-0.10
Neutral
Varity_R
0.71
gMVP
0.92
Mutation Taster
=11/89
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs727502768; hg19: chr16-79633594; API