chr3-49718412-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_198722.3(AMIGO3):ā€‹c.1054T>Gā€‹(p.Cys352Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,612,928 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 (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.000016 ( 0 hom. )

Consequence

AMIGO3
NM_198722.3 missense

Scores

12
5
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.43
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
AMIGO3NM_198722.3 linkuse as main transcriptc.1054T>G p.Cys352Gly missense_variant 1/1 ENST00000320431.8
RNF123NM_022064.5 linkuse as main transcriptc.3500+1935A>C intron_variant ENST00000327697.11
RNF123NR_135218.2 linkuse as main transcriptn.3826+1935A>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
AMIGO3ENST00000320431.8 linkuse as main transcriptc.1054T>G p.Cys352Gly missense_variant 1/1 NM_198722.3 P1
RNF123ENST00000327697.11 linkuse as main transcriptc.3500+1935A>C intron_variant 1 NM_022064.5 P1Q5XPI4-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152236
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000360
AC:
9
AN:
249888
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135472
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1460692
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
726680
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152236
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 16, 2024The c.1054T>G (p.C352G) alteration is located in exon 1 (coding exon 1) of the AMIGO3 gene. This alteration results from a T to G substitution at nucleotide position 1054, causing the cysteine (C) at amino acid position 352 to be replaced by a glycine (G). 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
0.81
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.44
CADD
Uncertain
25
DANN
Uncertain
0.97
DEOGEN2
Uncertain
0.43
T
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Benign
0.47
T
M_CAP
Pathogenic
0.42
D
MetaRNN
Pathogenic
0.80
D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Pathogenic
3.4
M
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-8.4
D
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.33
MutPred
0.87
Loss of stability (P = 0.0059);
MVP
1.0
ClinPred
0.82
D
GERP RS
5.4
Varity_R
0.94
gMVP
1.0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776880189; hg19: chr3-49755845; API