NM_005360.5:c.895C>T

Variant names:

• chr16-79599008-G-A
• rs786205221
• NM_005360.5:c.895C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_005360.5(MAF):​c.895C>T​(p.Arg299Cys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R299G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MAF NM_005360.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.95
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 ClinVar as Likely_pathogenic. ClinVar VariationId is 190235.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 16-79599008-G-A is Pathogenic according to our data. Variant chr16-79599008-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1360617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAF	NM_005360.5	c.895C>T	p.Arg299Cys	missense_variant	Exon 1 of 2	ENST00000326043.5	NP_005351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAF	ENST00000326043.5	c.895C>T	p.Arg299Cys	missense_variant	Exon 1 of 2	1	NM_005360.5	ENSP00000327048.4
MAF	ENST00000569649.1	c.895C>T	p.Arg299Cys	missense_variant	Exon 1 of 2	5		ENSP00000455097.1
MAF	ENST00000393350.1	c.895C>T	p.Arg299Cys	missense_variant	Exon 1 of 1	6		ENSP00000377019.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ayme-Gripp syndrome;C1857768:Cataract 21 multiple types Pathogenic:1

Oct 04, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg299 amino acid residue in MAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17982426, 25064449). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine with cysteine at codon 299 of the MAF protein (p.Arg299Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with bilateral cataracts (Invitae). In at least one individual the variant was observed to be de novo. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. -

Cataract 21 multiple types Pathogenic:1

Feb 25, 2025

Clinical Genomics, G42 Labs

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.895C>T, p.(Arg299Cys) is a missense variant in the MAF gene, which results in the amino acid substitution of Cysteine for Arginine at codon 299. This variant is not present in the gnomAD database (gnomAD version 3.1.2). Multiple lines of computational evidence support a deleterious effect on the gene or gene product. The variant lies in the bZIP Maf transcription factor domain of the MAF protein (Uniprot ID: O75444). One clinical laboratory in ClinVar database has classified this variant as pathogenic (Variation ID: VCV001360617.6). A different missense p.(Arg299Ser) affecting the same codon has previously been reported among individuals with congenital cataractmicrocornea syndrome (PMID: 25064449, 17982426). Based on the above reasons, this variant is classified as Likely pathogenic. ACMG Criteria: PM2, PP3, PM1, PM5 - Likley Pathogenic -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	.;M;M
PhyloP100		2.0
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.92
MutPred		0.83		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		0.97
ClinPred		1.0	D
GERP RS		3.0
Varity_R		0.98
gMVP		0.89

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

Other links and lift over

dbSNP: rs786205221; hg19: chr16-79632905;