rs727502812

Positions:

• chr16-79599742-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_005360.5(MAF):​c.161C>T​(p.Ser54Leu) variant causes a missense change involving the alteration of a 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: MAF NM_005360.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:4
• 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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 16-79599742-G-A is Pathogenic according to our data. Variant chr16-79599742-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 162512.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-79599742-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAF	NM_005360.5	c.161C>T	p.Ser54Leu	missense_variant	1/2	ENST00000326043.5	NP_005351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAF	ENST00000326043.5	c.161C>T	p.Ser54Leu	missense_variant	1/2	1	NM_005360.5	ENSP00000327048	A2
MAF	ENST00000569649.1	c.161C>T	p.Ser54Leu	missense_variant	1/2	5		ENSP00000455097	P4
MAF	ENST00000393350.1	c.161C>T	p.Ser54Leu	missense_variant	1/1			ENSP00000377019	A2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2023

Published functional studies demonstrate a damaging effect (Niceta et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25865493, 33528093, 31328266, 31600839) -

MAF-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 10, 2024

The MAF c.161C>T variant is predicted to result in the amino acid substitution p.Ser54Leu. This variant has been reported to occur de novo in multiple unrelated individuals affected with Ayme-Gripp syndrome (see for example Niceta et al. 2015. PubMed ID: 25865493; Niceta et al. 2019. PubMed ID: 31600839; Chaudhry et al. 2021. PubMed ID: 33528093; Xu et al. 2021. PubMed ID: 34976764). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (ClinVar ID 162512). The c.161C>T (p.Ser54Leu) variant affects one of the four GSK3 phosphorylation motifs and was found to impair MAF phosphorylation and proteasomal degradation in vitro as well as induce neurodevelopmental defects in an in vivo (zebrafish) model (Niceta et al. 2015. PubMed ID: 25865493). Consistent with this, an alternate nucleotide substitution at the same amino acid position designated c.161C>G (p.Ser54Trp) was reported to occur de novo in a patient affected with Ayme-Gripp syndrome (Amudhavalli et al. 2018. PubMed ID: 30160832). Based on the available evidence, this variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;.;D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M;M
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.013	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.99, 0.99	.;D;D
Vest4		0.81
MutPred		0.23		Loss of glycosylation at S54 (P = 0.0135);Loss of glycosylation at S54 (P = 0.0135);Loss of glycosylation at S54 (P = 0.0135);
MVP		0.96
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.59
gMVP		0.82

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: rs727502766; hg19: chr16-79633639;