NM_198722.3:c.887T>C

Variant names:

• chr3-49718579-A-G
• rs780590724
• NM_198722.3:c.887T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_198722.3(AMIGO3):​c.887T>C​(p.Leu296Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,460,704 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: AMIGO3 NM_198722.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.01

Genes affected

AMIGO3 (HGNC:24075): (adhesion molecule with Ig like domain 3) Predicted to be involved in brain development and heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules. Predicted to act upstream of or within positive regulation of synapse assembly. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

RNF123 (HGNC:21148): (ring finger protein 123) The protein encoded by this gene contains a C-terminal RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions, and an N-terminal SPRY domain. This protein displays E3 ubiquitin ligase activity toward the cyclin-dependent kinase inhibitor 1B which is also known as p27 or KIP1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

GMPPB (HGNC:22932): (GDP-mannose pyrophosphorylase B) This gene is thought to encode a GDP-mannose pyrophosphorylase. The encoded protein catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, a reaction involved in the production of N-linked oligosaccharides. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMIGO3	NM_198722.3	c.887T>C	p.Leu296Pro	missense_variant	Exon 1 of 1	ENST00000320431.8	NP_942015.1
RNF123	NM_022064.5	c.3501-1932A>G		intron_variant	Intron 35 of 38	ENST00000327697.11	NP_071347.2
RNF123	NR_135218.2	n.3827-1932A>G		intron_variant	Intron 35 of 38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMIGO3	ENST00000320431.8	c.887T>C	p.Leu296Pro	missense_variant	Exon 1 of 1	6	NM_198722.3	ENSP00000323096.7
RNF123	ENST00000327697.11	c.3501-1932A>G		intron_variant	Intron 35 of 38	1	NM_022064.5	ENSP00000328287.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000161 AC: 4 AN: 248960 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135174

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460704 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726688

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.887T>C (p.L296P) alteration is located in exon 1 (coding exon 1) of the AMIGO3 gene. This alteration results from a T to C substitution at nucleotide position 887, causing the leucine (L) at amino acid position 296 to be replaced by a proline (P). 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	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.1	M
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.87
MutPred		0.83		Loss of stability (P = 0.0332);
MVP		1.0
ClinPred		0.95	D
GERP RS		4.2
Varity_R		0.88
gMVP		0.99

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: rs780590724; hg19: chr3-49756012;