17-81922673-C-T

Variant names:

• chr17-81922673-C-T
• rs774502626
• NM_002359.4:c.421G>A

Variant summary

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

The NM_002359.4(MAFG):​c.421G>A​(p.Val141Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,506,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MAFG NM_002359.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

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=0.05777979).
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAFG	NM_002359.4	c.421G>A	p.Val141Ile	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.421G>A	p.Val141Ile	missense_variant	Exon 3 of 3	1	NM_002359.4	ENSP00000350369.4
MAFG	ENST00000392366.7	c.421G>A	p.Val141Ile	missense_variant	Exon 3 of 3	1		ENSP00000376173.3
MAFG	ENST00000574686.1	c.*125G>A		downstream_gene_variant		5		ENSP00000459634.1
ENSG00000264769	ENST00000580897.1	n.-226C>T		upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000214 AC: 3 AN: 140494 Hom.: 0 AF XY: 0.0000398 AC XY: 3 AN XY: 75368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000294

Gnomad OTH exome AF: 0.000316

GnomAD4 exome AF: 0.0000103 AC: 14 AN: 1354626 Hom.: 0 Cov.: 32 AF XY: 0.00000902 AC XY: 6 AN XY: 664888

Gnomad4 AFR exome AF: 0.0000682

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000289

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000751

Gnomad4 OTH exome AF: 0.0000360

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74338

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.421G>A (p.V141I) 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 421, causing the valine (V) at amino acid position 141 to be replaced by an isoleucine (I). 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	0.073
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.080	T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	-0.20	N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.17
Sift	Benign	0.87	T;T
Sift4G	Benign	0.49	T;T
Polyphen		0.0	B;B
Vest4		0.088
MutPred		0.23		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		0.27
MPC		0.69
ClinPred		0.047	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.080
gMVP		0.23

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: rs774502626; hg19: chr17-79880549;