rs1555530022

Positions:

• chr16-79599590-CCTCGGGGTTCAGCTGCTG-CTGCA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005360.5(MAF):​c.295_312delinsTGCA​(p.Gln99CysfsTer272) variant causes a frameshift 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 (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: MAF NM_005360.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.79

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 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-79599591-CTCGGGGTTCAGCTGCTG-TGCA is Pathogenic according to our data. Variant chr16-79599591-CTCGGGGTTCAGCTGCTG-TGCA is described in ClinVar as [Pathogenic]. Clinvar id is 541764.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAF	NM_005360.5	c.295_312delinsTGCA	p.Gln99CysfsTer272	frameshift_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.295_312delinsTGCA	p.Gln99CysfsTer272	frameshift_variant	1/2	1	NM_005360.5	ENSP00000327048	A2
MAF	ENST00000393350.1	c.295_312delinsTGCA	p.Gln99CysfsTer279	frameshift_variant	1/1			ENSP00000377019	A2
MAF	ENST00000569649.1	c.295_312delinsTGCA	p.Gln99CysfsTer?	frameshift_variant	1/2	5		ENSP00000455097	P4

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2019

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg294 amino acid residue in MAF. Other variant(s) that disrupt this residue have been observed in individuals with MAF-related conditions (PMID:24968223, 26694549, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. This variant has been observed to segregate with clinical features of MAF-related cataracts in a family (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the MAF gene (p.Leu101Argfs*63). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 305 amino acids of the MAF protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555530022; hg19: chr16-79633488;