8-143429368-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_201589.4(MAFA):c.1039G>T(p.Gly347Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0662 in 1,399,650 control chromosomes in the GnomAD database, including 3,387 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.046 (234 hom., cov: 32)
  • Exomes 𝑓: 0.069 (3153 hom.)
• Consequence: MAFA NM_201589.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.647

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014564693).
• BP6: Variant 8-143429368-C-A is Benign according to our data. Variant chr8-143429368-C-A is described in ClinVar as [Benign]. Clinvar id is 3055993.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAFA	NM_201589.4	c.1039G>T	p.Gly347Cys	missense_variant	1/1	ENST00000333480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAFA	ENST00000333480.3	c.1039G>T	p.Gly347Cys	missense_variant	1/1		NM_201589.4	P1
MAFA	ENST00000528185.1	n.389+142G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0459 AC: 6975 AN: 151944 Hom.: 234 Cov.: 32

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0459

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.0610

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0660

Gnomad OTH AF: 0.0489

GnomAD3 exomes AF: 0.0573 AC: 2015 AN: 35150 Hom.: 78 AF XY: 0.0568 AC XY: 1264 AN XY: 22234

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.0499

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.0846

Gnomad SAS exome AF: 0.0455

Gnomad FIN exome AF: 0.0576

Gnomad NFE exome AF: 0.0709

Gnomad OTH exome AF: 0.0568

GnomAD4 exome AF: 0.0686 AC: 85626 AN: 1247598 Hom.: 3153 Cov.: 30 AF XY: 0.0676 AC XY: 41462 AN XY: 613624

Gnomad4 AFR exome AF: 0.00947

Gnomad4 AMR exome AF: 0.0426

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.0456

Gnomad4 SAS exome AF: 0.0389

Gnomad4 FIN exome AF: 0.0511

Gnomad4 NFE exome AF: 0.0748

Gnomad4 OTH exome AF: 0.0585

GnomAD4 genome AF: 0.0459 AC: 6973 AN: 152052 Hom.: 234 Cov.: 32 AF XY: 0.0454 AC XY: 3374 AN XY: 74360

Gnomad4 AFR AF: 0.0124

Gnomad4 AMR AF: 0.0459

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.0612

Gnomad4 SAS AF: 0.0441

Gnomad4 FIN AF: 0.0498

Gnomad4 NFE AF: 0.0660

Gnomad4 OTH AF: 0.0479

Alfa AF: 0.0547 Hom.: 49

Bravo AF: 0.0443

TwinsUK AF: 0.0731 AC: 271

ALSPAC AF: 0.0807 AC: 311

ExAC AF: 0.0309 AC: 1440

Asia WGS AF: 0.0560 AC: 195 AN: 3438

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MAFA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.87	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.019	D
Sift4G	Benign	0.061	T
Polyphen		0.98	D
Vest4		0.091
ClinPred		0.016	T
GERP RS		3.0
Varity_R		0.37
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs62521874; hg19: chr8-144511538; COSMIC: COSV61087095;