7-1540310-G-A

Variant names:

• chr7-1540310-G-A
• NM_002360.4:c.406G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002360.4(MAFK):​c.406G>A​(p.Val136Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,256 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAFK NM_002360.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.73

Genes affected

MAFK (HGNC:6782): (MAF bZIP transcription factor K) The developmentally regulated expression of the globin genes depends on upstream regulatory elements termed locus control regions (LCRs). LCRs are associated with powerful enhancer activity that is mediated by the transcription factor NFE2 (nuclear factor erythroid-2). NFE2 recognition sites are also present in the gene promoters of 2 heme biosynthetic enzymes, porphobilinogen deaminase (PBGD; MIM 609806) and ferrochelatase (FECH; MIM 612386). NFE2 DNA-binding activity consists of a heterodimer containing an 18-kD Maf protein (MafF, MafG (MIM 602020), or MafK) and p45 (MIM 601490). Both subunits are members of the activator protein-1 superfamily of basic leucine zipper (bZIP) proteins (see MIM 165160). Maf homodimers suppress transcription at NFE2 sites.[supplied by OMIM, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAFK	NM_002360.4	c.406G>A	p.Val136Ile	missense_variant	Exon 3 of 3	ENST00000343242.9	NP_002351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAFK	ENST00000343242.9	c.406G>A	p.Val136Ile	missense_variant	Exon 3 of 3	1	NM_002360.4	ENSP00000344903.4
MAFK	ENST00000406174.2	c.406G>A	p.Val136Ile	missense_variant	Exon 3 of 3	3		ENSP00000385437.2
MAFK	ENST00000403150.5	n.406G>A		non_coding_transcript_exon_variant	Exon 3 of 4	2		ENSP00000386009.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459256 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725846

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.406G>A (p.V136I) alteration is located in exon 3 (coding exon 2) of the MAFK gene. This alteration results from a G to A substitution at nucleotide position 406, causing the valine (V) at amino acid position 136 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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.39	N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.071	T;T
Polyphen		1.0	D;D
Vest4		0.40
MutPred		0.25		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.85
MPC		1.6
ClinPred		0.89	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-1579946; COSMIC: COSV52474880; COSMIC: COSV52474880;