rs727502814

Variant names:

• chr16-79599730-G-A
• rs727502769
• NM_005360.5:c.173C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.09

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 14 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-79599731-T-C is described in Lovd as [Pathogenic].
• PP5: Variant 16-79599730-G-A is Pathogenic according to our data. Variant chr16-79599730-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 162514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-79599730-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAF	NM_005360.5	c.173C>T	p.Thr58Ile	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.173C>T	p.Thr58Ile	missense_variant	Exon 1 of 2	1	NM_005360.5	ENSP00000327048.4
MAF	ENST00000569649.1	c.173C>T	p.Thr58Ile	missense_variant	Exon 1 of 2	5		ENSP00000455097.1
MAF	ENST00000393350.1	c.173C>T	p.Thr58Ile	missense_variant	Exon 1 of 1	6		ENSP00000377019.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460626 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726676

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: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ayme-Gripp syndrome Pathogenic:2

May 07, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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

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

- -

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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	.;.;D
Eigen	Benign	0.16
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Uncertain	2.2	.;M;M
PrimateAI	Pathogenic	0.97	D
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.38, 0.26	.;B;B
Vest4		0.31
MutPred		0.089		Loss of glycosylation at T58 (P = 0.0079);Loss of glycosylation at T58 (P = 0.0079);Loss of glycosylation at T58 (P = 0.0079);
MVP		0.99
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.75
gMVP		0.88

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: rs727502769; hg19: chr16-79633627;