Genetic Variant MAF:p.Thr58Ile (chr16-79599730-G-A) – ACMG Classification: Pathogenic (15 pts)

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong

The NM_005360.5(MAF):c.173C>T(p.Thr58Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T58A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAF
NM_005360.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.09

Publications

10 publications found

Variant links:

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

MAF links:

ENSG00000278058 (HGNC:):

ENSG00000278058 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-79599731-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 162513.Status of the report is no_assertion_criteria_provided, 0 stars.

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.

PP5

Variant 16-79599730-G-A is Pathogenic according to our data. Variant chr16-79599730-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 162514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAF	NM_005360.5	MANE Select	c.173C>T	p.Thr58Ile	missense	Exon 1 of 2	NP_005351.2
	MAF	NM_001031804.3		c.173C>T	p.Thr58Ile	missense	Exon 1 of 1	NP_001026974.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MAF	ENST00000326043.5	TSL:1 MANE Select	c.173C>T	p.Thr58Ile	missense	Exon 1 of 2	ENSP00000327048.4
MAF	ENST00000569649.1	TSL:5	c.173C>T	p.Thr58Ile	missense	Exon 1 of 2	ENSP00000455097.1
MAF	ENST00000393350.1	TSL:6	c.173C>T	p.Thr58Ile	missense	Exon 1 of 1	ENSP00000377019.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1460626

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726676

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52448

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111894

Other (OTH)

AF:

0.00

AC:

AN:

60348

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ayme-Gripp syndrome

Pathogenic:2

May 07, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Reparto di Fisiopatologia delle Malattie Genetiche, Dipartimento di Ematologia, Oncologia; Istituto Superiore di Sanità

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:not provided

not provided

Pathogenic:2

Jan 11, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25865493, 12072800, 28482824, 36097645, 36477366, 34643041)

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

Eigen

Benign

0.16

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.97

MetaRNN

Uncertain

0.51

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.2

PhyloP100

7.1

PrimateAI

Pathogenic

0.97

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.38

Vest4

0.31

MutPred

0.089

Loss of glycosylation at T58 (P = 0.0079)

MVP

0.99

ClinPred

0.99

GERP RS

3.1

PromoterAI

-0.094

Neutral

(source)

Varity_R

0.75

gMVP

0.88

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over