3-65381879-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001033057.2(MAGI1):c.2699C>T(p.Ala900Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000101 in 1,606,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: MAGI1 NM_001033057.2 missense, splice_region
• Scores: Splicing: ADA: 0.6210
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.39

Genes affected

MAGI1 (HGNC:946): (membrane associated guanylate kinase, WW and PDZ domain containing 1) The protein encoded by this gene is a member of the membrane-associated guanylate kinase homologue (MAGUK) family. MAGUK proteins participate in the assembly of multiprotein complexes on the inner surface of the plasma membrane at regions of cell-cell contact. The product of this gene may play a role as scaffolding protein at cell-cell junctions. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

LOC124906246 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.086080074).
• BS2: High AC in GnomAd at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGI1	NM_001033057.2	c.2699C>T	p.Ala900Val	missense_variant, splice_region_variant	16/23	ENST00000402939.7
LOC124906246	XR_007095952.1	n.78+753G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGI1	ENST00000402939.7	c.2699C>T	p.Ala900Val	missense_variant, splice_region_variant	16/23	1	NM_001033057.2	A2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152124 Hom.: 0 Cov.: 32

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: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000206 AC: 50 AN: 243224 Hom.: 0 AF XY: 0.000266 AC XY: 35 AN XY: 131480

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000239

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.000103

Gnomad FIN exome AF: 0.000471

Gnomad NFE exome AF: 0.000228

Gnomad OTH exome AF: 0.000504

GnomAD4 exome AF: 0.000101 AC: 147 AN: 1454494 Hom.: 0 Cov.: 30 AF XY: 0.000113 AC XY: 82 AN XY: 723084

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000354

Gnomad4 FIN exome AF: 0.000564

Gnomad4 NFE exome AF: 0.0000830

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74442

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: 0.000660

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000896 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2021

The c.2699C>T (p.A900V) alteration is located in exon 16 (coding exon 16) of the MAGI1 gene. This alteration results from a C to T substitution at nucleotide position 2699, causing the alanine (A) at amino acid position 900 to be replaced by a valine (V). 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
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.41
Cadd	Pathogenic	31
Dann	Uncertain	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.086	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	L;.;.;.;.;L;.;.
MutationTaster	Benign	0.55	D;D;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N;.;.;N;N;N;N;N
REVEL	Benign	0.045
Sift	Uncertain	0.013	D;.;.;D;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T
Polyphen		0.77	P;.;.;B;.;P;B;.
Vest4		0.20
MVP		0.13
MPC		0.90
ClinPred		0.056	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.62
dbscSNV1_RF	Benign	0.59
SpliceAI score (max)		0.16		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: rs200362587; hg19: chr3-65367554; COSMIC: COSV58318552; COSMIC: COSV58318552;