3-49718222-C-T

Variant names:

• chr3-49718222-C-T
• rs1238728200
• NM_198722.3:c.1244G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198722.3(AMIGO3):​c.1244G>A​(p.Arg415His) 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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AMIGO3 NM_198722.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.644

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089399815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMIGO3	NM_198722.3	c.1244G>A	p.Arg415His	missense_variant	Exon 1 of 1	ENST00000320431.8	NP_942015.1
RNF123	NM_022064.5	c.3500+1745C>T		intron_variant	Intron 35 of 38	ENST00000327697.11	NP_071347.2
RNF123	NR_135218.2	n.3826+1745C>T		intron_variant	Intron 35 of 38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMIGO3	ENST00000320431.8	c.1244G>A	p.Arg415His	missense_variant	Exon 1 of 1	6	NM_198722.3	ENSP00000323096.7
RNF123	ENST00000327697.11	c.3500+1745C>T		intron_variant	Intron 35 of 38	1	NM_022064.5	ENSP00000328287.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1244G>A (p.R415H) alteration is located in exon 1 (coding exon 1) of the AMIGO3 gene. This alteration results from a G to A substitution at nucleotide position 1244, causing the arginine (R) at amino acid position 415 to be replaced by a histidine (H). 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	0.081
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.7
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.13
Sift	Benign	0.048	D
Sift4G	Benign	0.087	T
Polyphen		0.0	B
Vest4		0.069
MutPred		0.36		Loss of MoRF binding (P = 0.0065);
MVP		0.82
ClinPred		0.43	T
GERP RS		3.2
Varity_R		0.054
gMVP		0.30

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: rs1238728200; hg19: chr3-49755655;