7-1539956-G-A

Variant names:

• chr7-1539956-G-A
• NM_002360.4:c.52G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002360.4(MAFK):​c.52G>A​(p.Gly18Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30141538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAFK	NM_002360.4	c.52G>A	p.Gly18Ser	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.52G>A	p.Gly18Ser	missense_variant	Exon 3 of 3	1	NM_002360.4	ENSP00000344903.4
MAFK	ENST00000406174.2	c.52G>A	p.Gly18Ser	missense_variant	Exon 3 of 3	3		ENSP00000385437.2
MAFK	ENST00000403150.5	n.52G>A		non_coding_transcript_exon_variant	Exon 3 of 4	2		ENSP00000386009.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1383456 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 680032

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.52G>A (p.G18S) 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 52, causing the glycine (G) at amino acid position 18 to be replaced by a serine (S). 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	0.10
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.063	T;T
Eigen	Benign	0.049
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	.;T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.43
Sift	Benign	0.34	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.010	B;B
Vest4		0.49
MutPred		0.11		Gain of phosphorylation at G18 (P = 0.0208);Gain of phosphorylation at G18 (P = 0.0208);
MVP		0.73
MPC		0.88
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.26
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr7-1579592;