16-79599008-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_005360.5(MAF):​c.895C>G​(p.Arg299Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R299S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 30)

Consequence

MAF
NM_005360.5 missense

Scores

14
4
1

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.95
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a region_of_interest Basic motif (size 25) in uniprot entity MAF_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_005360.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-79599008-G-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAFNM_005360.5 linkc.895C>G p.Arg299Gly 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.895C>G p.Arg299Gly missense_variant Exon 1 of 2 1 NM_005360.5 ENSP00000327048.4 O75444-1
MAFENST00000569649.1 linkc.895C>G p.Arg299Gly missense_variant Exon 1 of 2 5 ENSP00000455097.1 H3BP11
MAFENST00000393350.1 linkc.895C>G p.Arg299Gly missense_variant Exon 1 of 1 6 ENSP00000377019.1 O75444-2

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Cov.:
37
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

MAF-related disorder Uncertain:1
Feb 27, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The MAF c.895C>G variant is predicted to result in the amino acid substitution p.Arg299Gly. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note a different variant impacting the same amino acid (p.Arg299Ser) has been documented in patients with cataracts (Vanita et al. 2014. PubMed ID: 25064449). At this time, the clinical significance of the p.Arg229Gly variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
.;.;D
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Pathogenic
0.86
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.4
.;M;M
PrimateAI
Pathogenic
0.94
D
PROVEAN
Pathogenic
-6.8
D;D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.92
MutPred
0.84
Loss of methylation at R299 (P = 0.0237);Loss of methylation at R299 (P = 0.0237);Loss of methylation at R299 (P = 0.0237);
MVP
0.96
ClinPred
1.0
D
GERP RS
3.0
Varity_R
0.99
gMVP
0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-79632905; API