3-49718331-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_198722.3(AMIGO3):​c.1135G>A​(p.Glu379Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

AMIGO3
NM_198722.3 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.68
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2291703).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AMIGO3NM_198722.3 linkc.1135G>A p.Glu379Lys missense_variant Exon 1 of 1 ENST00000320431.8 NP_942015.1 Q86WK7
RNF123NM_022064.5 linkc.3500+1854C>T intron_variant Intron 35 of 38 ENST00000327697.11 NP_071347.2 Q5XPI4-1
RNF123NR_135218.2 linkn.3826+1854C>T intron_variant Intron 35 of 38

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AMIGO3ENST00000320431.8 linkc.1135G>A p.Glu379Lys missense_variant Exon 1 of 1 6 NM_198722.3 ENSP00000323096.7 Q86WK7
RNF123ENST00000327697.11 linkc.3500+1854C>T intron_variant Intron 35 of 38 1 NM_022064.5 ENSP00000328287.6 Q5XPI4-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000682
AC:
17
AN:
249436
Hom.:
0
AF XY:
0.0000813
AC XY:
11
AN XY:
135220
show subpopulations
Gnomad AFR exome
AF:
0.0000618
Gnomad AMR exome
AF:
0.000318
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:
0.0000446
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000294
AC:
43
AN:
1461038
Hom.:
0
Cov.:
31
AF XY:
0.0000275
AC XY:
20
AN XY:
726864
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000425
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000189
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000125
Hom.:
0
Bravo
AF:
0.0000718
ExAC
AF:
0.0000330
AC:
4

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 28, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1135G>A (p.E379K) 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 1135, causing the glutamic acid (E) at amino acid position 379 to be replaced by a lysine (K). 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
0.15
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.10
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.044
T
Eigen
Benign
-0.081
Eigen_PC
Benign
-0.12
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.70
T
M_CAP
Uncertain
0.24
D
MetaRNN
Benign
0.23
T
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Pathogenic
2.9
M
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-2.1
N
REVEL
Uncertain
0.38
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.017
D
Polyphen
0.81
P
Vest4
0.21
MutPred
0.38
Gain of ubiquitination at E379 (P = 0.0198);
MVP
0.94
ClinPred
0.25
T
GERP RS
4.7
Varity_R
0.19
gMVP
0.83

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

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

Other links and lift over

dbSNP: rs747670903; hg19: chr3-49755764; API