12-47077994-T-A

Variant names:

• chr12-47077994-T-A
• NM_001370299.1:c.1009A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001370299.1(AMIGO2):​c.1009A>T​(p.Met337Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AMIGO2 NM_001370299.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.256

Genes affected

AMIGO2 (HGNC:24073): (adhesion molecule with Ig like domain 2) Predicted to be involved in several processes, including heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules; homophilic cell adhesion via plasma membrane adhesion molecules; and negative regulation of programmed cell death. Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be located in nucleus and plasma membrane. Predicted to be integral component of membrane. Biomarker of gastric adenocarcinoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04276374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMIGO2	NM_001370299.1	c.1009A>T	p.Met337Leu	missense_variant	Exon 3 of 3	ENST00000550413.2	NP_001357228.1
AMIGO2	NM_001143668.1	c.1009A>T	p.Met337Leu	missense_variant	Exon 3 of 3		NP_001137140.1
AMIGO2	NM_181847.4	c.1009A>T	p.Met337Leu	missense_variant	Exon 2 of 2		NP_862830.1
AMIGO2	XM_047428785.1	c.1009A>T	p.Met337Leu	missense_variant	Exon 2 of 2		XP_047284741.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMIGO2	ENST00000550413.2	c.1009A>T	p.Met337Leu	missense_variant	Exon 3 of 3	1	NM_001370299.1	ENSP00000449034.1
AMIGO2	ENST00000266581.4	c.1009A>T	p.Met337Leu	missense_variant	Exon 2 of 2	1		ENSP00000266581.4
AMIGO2	ENST00000429635.1	c.1009A>T	p.Met337Leu	missense_variant	Exon 3 of 3	1		ENSP00000406020.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461580 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727094

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1009A>T (p.M337L) alteration is located in exon 2 (coding exon 1) of the AMIGO2 gene. This alteration results from a A to T substitution at nucleotide position 1009, causing the methionine (M) at amino acid position 337 to be replaced by a leucine (L). 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	0.087
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.1
DANN	Benign	0.83
DEOGEN2	Benign	0.020	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.49	.;.;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.32	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.072
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.089
MutPred		0.45		Gain of catalytic residue at N339 (P = 0.0217);Gain of catalytic residue at N339 (P = 0.0217);Gain of catalytic residue at N339 (P = 0.0217);
MVP		0.12
MPC		0.38
ClinPred		0.16	T
GERP RS		-5.6
Varity_R		0.079
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-47471777;