rs1555530022

Variant names:

• chr16-79599591-CTCGGGGTTCAGCTGCTG-TGCA
• rs1555530022
• NM_005360.5:c.295_312delCAGCAGCTGAACCCCGAGinsTGCA

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_312delCAGCAGCTGAACCCCGAGinsTGCA​(p.Gln99CysfsTer272) variant causes a frameshift, 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 (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: MAF NM_005360.5 frameshift, missense
• 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 rank	MANE	Protein	UniProt
MAF	NM_005360.5	c.295_312delCAGCAGCTGAACCCCGAGinsTGCA	p.Gln99CysfsTer272	frameshift_variant, missense_variant	Exon 1 of 2	ENST00000326043.5	NP_005351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAF	ENST00000326043.5	c.295_312delCAGCAGCTGAACCCCGAGinsTGCA	p.Gln99CysfsTer272	frameshift_variant, missense_variant	Exon 1 of 2	1	NM_005360.5	ENSP00000327048.4
MAF	ENST00000569649.1	c.295_312delCAGCAGCTGAACCCCGAGinsTGCA	p.Gln99CysfsTer303	frameshift_variant, missense_variant	Exon 1 of 2	5		ENSP00000455097.1
MAF	ENST00000393350.1	c.295_312delCAGCAGCTGAACCCCGAGinsTGCA	p.Gln99CysfsTer279	frameshift_variant, missense_variant	Exon 1 of 1	6		ENSP00000377019.1

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

Jul 26, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with clinical features of MAF-related cataracts in a family (Invitae). 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. For these reasons, this variant has been classified as Pathogenic. -

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;