3-49718427-C-T

Position:

• chr3-49718427-C-T

Variant summary

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

The NM_198722.3(AMIGO3):​c.1039G>A​(p.Ala347Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: AMIGO3 NM_198722.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.127

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=0.16718993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AMIGO3	NM_198722.3	c.1039G>A	p.Ala347Thr	missense_variant	1/1	ENST00000320431.8	NP_942015.1
RNF123	NM_022064.5	c.3500+1950C>T		intron_variant		ENST00000327697.11	NP_071347.2
RNF123	NR_135218.2	n.3826+1950C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AMIGO3	ENST00000320431.8	c.1039G>A	p.Ala347Thr	missense_variant	1/1		NM_198722.3	ENSP00000323096	P1
RNF123	ENST00000327697.11	c.3500+1950C>T		intron_variant		1	NM_022064.5	ENSP00000328287	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460632 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726636

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.1039G>A (p.A347T) 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 1039, causing the alanine (A) at amino acid position 347 to be replaced by a threonine (T). 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	0.097
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.10
Sift	Benign	0.13	T
Sift4G	Benign	0.12	T
Polyphen		0.017	B
Vest4		0.034
MutPred		0.43		Gain of loop (P = 0.2754);
MVP		0.93
ClinPred		0.059	T
GERP RS		2.3
Varity_R		0.075
gMVP		0.80

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

Other links and lift over

dbSNP: rs1408855629; hg19: chr3-49755860; COSMIC: COSV57539770; COSMIC: COSV57539770;