rs727502766

Variant names:

• chr16-79599742-G-A
• rs727502766
• NM_005360.5:c.161C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

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 (★★). ClinVar reports functional evidence for this variant: "SCV005904762: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID:25865493)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MAF NM_005360.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.85
• Publications: 10 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), G2P, Ambry Genetics
• 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

ENSG00000278058 (HGNC:):

ACMG classification

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

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005904762: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 25865493).; SCV003842423: Published functional studies demonstrate a damaging effect (Niceta et al., 2015); PMID: 25865493; SCV005341302: "This 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)."
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_005360.5
• PM2: Very rare variant in population databases, with high coverage
• 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 cataract 21 multiple types, Ayme-Gripp syndrome, cataract - microcornea syndrome, Fine-Lubinsky syndrome, cerulean cataract, pulverulent cataract.
• 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 VariationId is 162512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAF	NM_005360.5	MANE Select	c.161C>T	p.Ser54Leu	missense	Exon 1 of 2	NP_005351.2
	MAF	NM_001031804.3		c.161C>T	p.Ser54Leu	missense	Exon 1 of 1	NP_001026974.1	O75444-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAF	ENST00000326043.5	TSL:1 MANE Select	c.161C>T	p.Ser54Leu	missense	Exon 1 of 2	ENSP00000327048.4	O75444-1
	MAF	ENST00000569649.1	TSL:5	c.161C>T	p.Ser54Leu	missense	Exon 1 of 2	ENSP00000455097.1	H3BP11
	MAF	ENST00000393350.1	TSL:6	c.161C>T	p.Ser54Leu	missense	Exon 1 of 1	ENSP00000377019.1	O75444-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Ayme-Gripp syndrome (3)
1	-	-	MAF-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.8
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.81
MutPred		0.23		Loss of glycosylation at S54 (P = 0.0135)
MVP		0.96
ClinPred		0.98	D
GERP RS		3.1
PromoterAI		0.0030	Neutral
Varity_R		0.59
gMVP		0.82
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs727502766; hg19: chr16-79633639;