8-143429956-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_201589.4(MAFA):c.451C>T(p.His151Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0011 in 1,276,216 control chromosomes in the GnomAD database, including 21 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 0.0059 (12 hom., cov: 30)
  • Exomes 𝑓: 0.00047 (9 hom.)
• Consequence: MAFA NM_201589.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.71

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=0.007215172).
• BP6: Variant 8-143429956-G-A is Benign according to our data. Variant chr8-143429956-G-A is described in ClinVar as [Benign]. Clinvar id is 1336773.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00588 (879/149498) while in subpopulation AFR AF= 0.0204 (840/41158). AF 95% confidence interval is 0.0193. There are 12 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 872 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAFA	NM_201589.4	c.451C>T	p.His151Tyr	missense_variant	1/1	ENST00000333480.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAFA	ENST00000333480.3	c.451C>T	p.His151Tyr	missense_variant	1/1		NM_201589.4	P1

Frequencies

GnomAD3 genomes AF: 0.00584 AC: 872 AN: 149390 Hom.: 12 Cov.: 30

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00179

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: 0.000105

Gnomad OTH AF: 0.00243

GnomAD3 exomes AF: 0.000662 AC: 18 AN: 27192 Hom.: 1 AF XY: 0.0000582 AC XY: 1 AN XY: 17172

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.00159

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000468 AC: 527 AN: 1126718 Hom.: 9 Cov.: 34 AF XY: 0.000392 AC XY: 214 AN XY: 546446

Gnomad4 AFR exome AF: 0.0195

Gnomad4 AMR exome AF: 0.000887

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000102

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000636

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00588 AC: 879 AN: 149498 Hom.: 12 Cov.: 30 AF XY: 0.00540 AC XY: 394 AN XY: 72942

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.00179

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000105

Gnomad4 OTH AF: 0.00241

Alfa AF: 0.00341 Hom.: 0

ESP6500AA AF: 0.0161 AC: 58

ESP6500EA AF: 0.000142 AC: 1

ExAC AF: 0.000626 AC: 53

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 17, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.015
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0072	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.97	D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.88	N
REVEL	Uncertain	0.42
Sift	Benign	0.70	T
Sift4G	Benign	1.0	T
Polyphen		0.99	D
Vest4		0.39
MVP		0.65
ClinPred		0.073	T
GERP RS		2.4
Varity_R		0.11
gMVP		0.62

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

Other links and lift over

dbSNP: rs149797559; hg19: chr8-144512126;