rs1555530080

Positions:

• chr16-79599733-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_005360.5(MAF):​c.170C>T​(p.Ser57Phe) 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAF NM_005360.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts 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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a region_of_interest Disordered (size 27) in uniprot entity MAF_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_005360.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761
• PP5: Variant 16-79599733-G-A is Pathogenic according to our data. Variant chr16-79599733-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAF	NM_005360.5	c.170C>T	p.Ser57Phe	missense_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.170C>T	p.Ser57Phe	missense_variant	1/2	1	NM_005360.5	ENSP00000327048	A2
MAF	ENST00000569649.1	c.170C>T	p.Ser57Phe	missense_variant	1/2	5		ENSP00000455097	P4
MAF	ENST00000393350.1	c.170C>T	p.Ser57Phe	missense_variant	1/1			ENSP00000377019	A2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460622 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.170C>T (p.S57F) alteration is located in coding exon 1 of the MAF gene. This alteration results from a C to T substitution at nucleotide position 170, causing the serine (S) at amino acid position 57 to be replaced by a phenylalanine (F). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the MAF c.170C>T alteration was not observed, with coverage at this position. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was detected in a patient with congenital cataracts, sensorineural hearing loss, reduced growth, and flat face in addition to other features consistent with Ayme-Gripp syndrome (Niceta, 2020). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.S57 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.S57F alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 19, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31600839) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	.;.;D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.97	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.54
MutPred		0.26		Loss of glycosylation at S57 (P = 0.0018);Loss of glycosylation at S57 (P = 0.0018);Loss of glycosylation at S57 (P = 0.0018);
MVP		0.97
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.76
gMVP		0.89

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: rs1555530080; hg19: chr16-79633630;