rs727502768

Positions:

• chr16-79599697-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Ayme-Gripp syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	not provided	Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 07, 2015	- -

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: 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
MutationTaster	Benign	0.99	D;D;D
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
Varity_R		0.71
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs727502768; hg19: chr16-79633594;