rs889770732

Variant names:

• chr1-113641930-C-G
• rs889770732
• NM_001142782.2:c.1380C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-113641930-C-G
• chr1-113641930-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001142782.2(MAGI3):​c.1380C>G​(p.Ile460Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,588,272 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 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MAGI3 NM_001142782.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75
• Publications: 0 publications found

Genes affected

MAGI3 (HGNC:29647): (membrane associated guanylate kinase, WW and PDZ domain containing 3) Predicted to enable frizzled binding activity. Predicted to be involved in signal transduction. Predicted to act upstream of or within positive regulation of JUN kinase activity. Located in cell junction. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142782.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGI3	NM_001142782.2	MANE Select	c.1380C>G	p.Ile460Met	missense	Exon 10 of 21	NP_001136254.1	Q5TCQ9-4
	MAGI3	NM_152900.3		c.1380C>G	p.Ile460Met	missense	Exon 10 of 21	NP_690864.2	Q5TCQ9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGI3	ENST00000307546.14	TSL:5 MANE Select	c.1380C>G	p.Ile460Met	missense	Exon 10 of 21	ENSP00000304604.9	Q5TCQ9-4
	MAGI3	ENST00000369617.8	TSL:1	c.1455C>G	p.Ile485Met	missense	Exon 11 of 22	ENSP00000358630.4	Q5TCQ9-2
	MAGI3	ENST00000369611.4	TSL:1	c.1380C>G	p.Ile460Met	missense	Exon 10 of 21	ENSP00000358624.4	Q5TCQ9-3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436146 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708462

African (AFR) AF: 0.00 AC: 0 AN: 33072

American (AMR) AF: 0.00 AC: 0 AN: 44162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25830

East Asian (EAS) AF: 0.00 AC: 0 AN: 38972

South Asian (SAS) AF: 0.00 AC: 0 AN: 84838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091290

Other (OTH) AF: 0.00 AC: 0 AN: 59174

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152126 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		1.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.65		Gain of catalytic residue at V456 (P = 0.0721)
MVP		0.68
MPC		0.68
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.63
gMVP		0.67
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs889770732; hg19: chr1-114184552;