Genetic Variant NM_201589.4:c.301C>A (chr8-143430106-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_201589.4(MAFA):c.301C>A(p.Pro101Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000288 in 1,145,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MAFA
NM_201589.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.58

Publications

0 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.19214651).

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAFA	NM_201589.4 link	c.301C>A	p.Pro101Thr	missense_variant	Exon 1 of 1	ENST00000333480.3	NP_963883.2	Q8NHW3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAFA	ENST00000333480.3 link	c.301C>A	p.Pro101Thr	missense_variant	Exon 1 of 1	6	NM_201589.4	ENSP00000328364.2		Q8NHW3
MAFA	ENST00000528185.1 link	n.-208C>A		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000120

AC:

AN:

142180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000433

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

13326

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000159

AC:

AN:

1003554

Hom.:

Cov.:

AF XY:

0.0000209

AC XY:

AN XY:

478880

show subpopulations

African (AFR)

AF:

0.000769

AC:

AN:

19504

American (AMR)

AF:

0.00

AC:

AN:

6082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11162

East Asian (EAS)

AF:

0.00

AC:

AN:

16734

South Asian (SAS)

AF:

0.00

AC:

AN:

25610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16728

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2548

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

868406

Other (OTH)

AF:

0.0000272

AC:

AN:

36780

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000120

AC:

AN:

142180

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

69122

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

39236

American (AMR)

AF:

0.00

AC:

AN:

14462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3352

East Asian (EAS)

AF:

0.00

AC:

AN:

4710

South Asian (SAS)

AF:

0.00

AC:

AN:

4628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8162

Middle Eastern (MID)

AF:

0.00

AC:

AN:

270

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64544

Other (OTH)

AF:

0.00

AC:

AN:

1950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000144

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 14, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.301C>A (p.P101T) alteration is located in exon 1 (coding exon 1) of the MAFA gene. This alteration results from a C to A substitution at nucleotide position 301, causing the proline (P) at amino acid position 101 to be replaced by a threonine (T). 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

0.064

BayesDel_addAF

Benign

0.0069

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.25

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.45

M_CAP

Pathogenic

0.99

MetaRNN

Benign

0.19

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

0.0

PhyloP100

1.6

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.36

Sift

Benign

0.047

Sift4G

Uncertain

0.032

Polyphen

0.0050

Vest4

0.075

MutPred

0.19

Gain of phosphorylation at P101 (P = 0.0174);

MVP

0.43

ClinPred

0.14

GERP RS

3.3

Varity_R

0.055

gMVP

0.43

Mutation Taster

=90/10

polymorphism

(source)

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

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NM_201589.4:c.301C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over