16-79599727-G-A

Position:

• chr16-79599727-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_005360.5(MAF):​c.176C>T​(p.Pro59Leu) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P59H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MAF NM_005360.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• 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 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 chr16-79599727-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 162515.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 16-79599727-G-A is Pathogenic according to our data. Variant chr16-79599727-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 162516.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-79599727-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAF	NM_005360.5	c.176C>T	p.Pro59Leu	missense_variant	1/2	ENST00000326043.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAF	ENST00000326043.5	c.176C>T	p.Pro59Leu	missense_variant	1/2	1	NM_005360.5	A2
MAF	ENST00000569649.1	c.176C>T	p.Pro59Leu	missense_variant	1/2	5		P4
MAF	ENST00000393350.1	c.176C>T	p.Pro59Leu	missense_variant	1/1			A2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Benign	0.97
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-4.7	D;D;D
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.064	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.41
MutPred		0.17		Loss of glycosylation at P59 (P = 0.0127);Loss of glycosylation at P59 (P = 0.0127);Loss of glycosylation at P59 (P = 0.0127);
MVP		1.0
ClinPred		0.97	D
GERP RS		4.1
Varity_R		0.47
gMVP		0.84

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: rs727502770; hg19: chr16-79633624;