17-81922691-C-T

Variant names:

• chr17-81922691-C-T
• rs763502860
• NM_002359.4:c.403G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002359.4(MAFG):​c.403G>A​(p.Ala135Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,508,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MAFG NM_002359.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

Genes affected

MAFG (HGNC:6781): (MAF bZIP transcription factor G) Globin gene expression is regulated through nuclear factor erythroid-2 (NFE2) elements located in enhancer-like locus control regions positioned many kb upstream of alpha- and beta-gene clusters (summarized by Blank et al., 1997 [PubMed 9166829]). NFE2 DNA-binding activity consists of a heterodimer containing a ubiquitous small Maf protein (MafF, MIM 604877; MafG; or MafK, MIM 600197) and the tissue-restricted protein p45 NFE2 (MIM 601490). Both subunits are members of the activator protein-1-like superfamily of basic leucine zipper (bZIP) proteins (see MIM 165160).[supplied by OMIM, Mar 2010]

ENSG00000264769 (HGNC:56705): (MAFG antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05029869).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAFG	NM_002359.4	c.403G>A	p.Ala135Thr	missense_variant	Exon 3 of 3	ENST00000357736.9	NP_002350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAFG	ENST00000357736.9	c.403G>A	p.Ala135Thr	missense_variant	Exon 3 of 3	1	NM_002359.4	ENSP00000350369.4
MAFG	ENST00000392366.7	c.403G>A	p.Ala135Thr	missense_variant	Exon 3 of 3	1		ENSP00000376173.3
MAFG	ENST00000574686.1	c.*107G>A		downstream_gene_variant		5		ENSP00000459634.1
ENSG00000264769	ENST00000580897.1	n.-208C>T		upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000457 AC: 6 AN: 131278 Hom.: 0 AF XY: 0.0000422 AC XY: 3 AN XY: 71120

Gnomad AFR exome AF: 0.000427

Gnomad AMR exome AF: 0.0000673

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000707

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000177 AC: 24 AN: 1356218 Hom.: 0 Cov.: 32 AF XY: 0.0000195 AC XY: 13 AN XY: 666384

Gnomad4 AFR exome AF: 0.000238

Gnomad4 AMR exome AF: 0.0000824

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000141

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74338

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ExAC AF: 0.0000258 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.403G>A (p.A135T) alteration is located in exon 3 (coding exon 2) of the MAFG gene. This alteration results from a G to A substitution at nucleotide position 403, causing the alanine (A) at amino acid position 135 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.089	T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.71	.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.11	N;N
REVEL	Benign	0.070
Sift	Benign	0.16	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.0040	B;B
Vest4		0.13
MutPred		0.21		Gain of glycosylation at A135 (P = 0.0364);Gain of glycosylation at A135 (P = 0.0364);
MVP		0.40
MPC		0.83
ClinPred		0.019	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Varity_R		0.028
gMVP		0.45

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: rs763502860; hg19: chr17-79880567;