Variant 16-79599008-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_005360.5(MAF):c.895C>A(p.Arg299Ser) variant causes a missense change involving the alteration of a non-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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R299G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 30)

Failed GnomAD Quality Control

Consequence

MAF
NM_005360.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.95

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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, 7 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 chr16-79599008-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1360617.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 16-79599008-G-T is Pathogenic according to our data. Variant chr16-79599008-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190235.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-79599008-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAF	NM_005360.5 linkuse as main transcript	c.895C>A	p.Arg299Ser	missense_variant	1/2	ENST00000326043.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAF	ENST00000326043.5 linkuse as main transcript	c.895C>A	p.Arg299Ser	missense_variant	1/2	1	NM_005360.5	A2	O75444-1
MAF	ENST00000569649.1 linkuse as main transcript	c.895C>A	p.Arg299Ser	missense_variant	1/2	5		P4
MAF	ENST00000393350.1 linkuse as main transcript	c.895C>A	p.Arg299Ser	missense_variant	1/1			A2	O75444-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

151802

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

151802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74166

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cataract 21 multiple types

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 18, 2007

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Jul 18, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

.;.;D

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Benign

0.73

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

.;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-5.8

D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.97

MutPred

0.83

Loss of methylation at R299 (P = 0.0237);Loss of methylation at R299 (P = 0.0237);Loss of methylation at R299 (P = 0.0237);

MVP

0.97

ClinPred

1.0

GERP RS

3.0

Varity_R

0.99

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over