Variant 8-143429660-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_201589.4(MAFA):c.747G>C(p.Lys249Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,584,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

MAFA
NM_201589.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0690

Variant links:

Genes affected

MAFA (HGNC:23145): (MAF bZIP transcription factor A) MAFA is a transcription factor that binds RIPE3b, a conserved enhancer element that regulates pancreatic beta cell-specific expression of the insulin gene (INS; MIM 176730) (Olbrot et al., 2002 [PubMed 12011435]).[supplied by OMIM, Mar 2008]

MAFA links:

MAFA (HGNC:):

MAFA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAFA	NM_201589.4 linkuse as main transcript	c.747G>C	p.Lys249Asn	missense_variant	1/1	ENST00000333480.3	NP_963883.2	Q8NHW3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAFA	ENST00000333480.3 linkuse as main transcript	c.747G>C	p.Lys249Asn	missense_variant	1/1	6	NM_201589.4	ENSP00000328364.2		Q8NHW3
MAFA	ENST00000528185.1 linkuse as main transcript	n.239G>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000147

AC:

AN:

203742

Hom.:

AF XY:

0.0000178

AC XY:

AN XY:

112522

show subpopulations

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:

0.0000328

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1432104

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

711654

show subpopulations

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:

0.0000259

Gnomad4 NFE exome

AF:

0.0000136

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151994

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000586

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000167

AC:

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

Sep 27, 2022

The c.747G>C (p.K249N) alteration is located in exon 1 (coding exon 1) of the MAFA gene. This alteration results from a G to C substitution at nucleotide position 747, causing the lysine (K) at amino acid position 249 to be replaced by an asparagine (N). 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

Pathogenic

1.0

BayesDel_addAF

Benign

0.0072

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

Eigen

Benign

0.077

Eigen_PC

Benign

0.0036

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.51

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

0.99

PrimateAI

Pathogenic

0.97

PROVEAN

Pathogenic

-4.4

REVEL

Uncertain

0.56

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.56

Vest4

0.70

MutPred

0.45

Loss of ubiquitination at K249 (P = 0.0283);

MVP

0.77

ClinPred

0.88

GERP RS

2.2

Varity_R

0.97

gMVP

0.65

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