Variant 7-1540293-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_002360.4(MAFK):c.389A>G(p.Lys130Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,459,408 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 0.0000082 ( 0 hom. )

Consequence

MAFK
NM_002360.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.88

Variant links:

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]

MAFK links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) (size 0) in uniprot entity MAFK_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.2556551).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAFK	NM_002360.4 linkuse as main transcript	c.389A>G	p.Lys130Arg	missense_variant	3/3	ENST00000343242.9	NP_002351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MAFK	ENST00000343242.9 linkuse as main transcript	c.389A>G	p.Lys130Arg	missense_variant	3/3	1	NM_002360.4	ENSP00000344903	P1
MAFK	ENST00000406174.2 linkuse as main transcript	c.389A>G	p.Lys130Arg	missense_variant	3/3	3		ENSP00000385437
MAFK	ENST00000403150.5 linkuse as main transcript	c.389A>G	p.Lys130Arg	missense_variant, NMD_transcript_variant	3/4	2		ENSP00000386009

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1459408

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726010

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2022

The c.389A>G (p.K130R) alteration is located in exon 3 (coding exon 2) of the MAFK gene. This alteration results from a A to G substitution at nucleotide position 389, causing the lysine (K) at amino acid position 130 to be replaced by an arginine (R). 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

0.077

BayesDel_addAF

Uncertain

0.082

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.064

T;T

Eigen

Benign

-0.061

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

.;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.82

N;N

REVEL

Uncertain

0.32

Sift

Benign

0.36

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.014

B;B

Vest4

0.10

MutPred

0.19

Loss of ubiquitination at K130 (P = 0.0174);Loss of ubiquitination at K130 (P = 0.0174);

MVP

0.81

MPC

0.69

ClinPred

0.67

GERP RS

5.1

Varity_R

0.23

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over