rs1555530080

Variant names:

• chr16-79599733-G-A
• rs1555530080
• NM_005360.5:c.170C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP2 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
• 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), Ambry Genetics, G2P
• 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 14 ACMG points.

• PM1: In a hotspot region, there are 8 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 cerulean cataract, Fine-Lubinsky syndrome, cataract 21 multiple types, Ayme-Gripp syndrome, pulverulent cataract, cataract - microcornea syndrome.
• 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 VariationId is 521242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAF	NM_005360.5	c.170C>T	p.Ser57Phe	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.170C>T	p.Ser57Phe	missense_variant	Exon 1 of 2	1	NM_005360.5	ENSP00000327048.4

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

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111890

Other (OTH) AF: 0.00 AC: 0 AN: 60344

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

Mar 12, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 19, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		8.8
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
PromoterAI		-0.042	Neutral
Varity_R		0.76
gMVP		0.89
Mutation Taster		=2/98	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: rs1555530080; hg19: chr16-79633630;