chr16-79599591-CTCGGGGTTCAGCTGCTG-TGCA

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PP2 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• 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
• Publications: 0 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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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.
• PP5: Variant 16-79599591-CTCGGGGTTCAGCTGCTG-TGCA is Pathogenic according to our data. Variant chr16-79599591-CTCGGGGTTCAGCTGCTG-TGCA is described in ClinVar as Pathogenic. ClinVar VariationId is 541764.Status of the report is criteria_provided_single_submitter, 1 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.295_312delCAGCAGCTGAACCCCGAGinsTGCA	p.Gln99CysfsTer272	frameshift missense	Exon 1 of 2	NP_005351.2
	MAF	NM_001031804.3		c.295_312delCAGCAGCTGAACCCCGAGinsTGCA	p.Gln99CysfsTer279	frameshift 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.295_312delCAGCAGCTGAACCCCGAGinsTGCA	p.Gln99CysfsTer272	frameshift missense	Exon 1 of 2	ENSP00000327048.4	O75444-1
	MAF	ENST00000569649.1	TSL:5	c.295_312delCAGCAGCTGAACCCCGAGinsTGCA	p.Gln99CysfsTer303	frameshift missense	Exon 1 of 2	ENSP00000455097.1	H3BP11
	MAF	ENST00000393350.1	TSL:6	c.295_312delCAGCAGCTGAACCCCGAGinsTGCA	p.Gln99CysfsTer279	frameshift missense	Exon 1 of 1	ENSP00000377019.1	O75444-2

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Ayme-Gripp syndrome;C1857768:Cataract 21 multiple types (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.8

Splicing

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

Other links and lift over

dbSNP: rs1555530022; hg19: chr16-79633488;