3-49718209-C-CCAGCGGCGG

Position:

• chr3-49718209-C-CCAGCGGCGG

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP3 BP6_Moderate BS2

The NM_198722.3(AMIGO3):​c.1256_1257insCCGCCGCTG​(p.Cys416_Arg418dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,612,336 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (6 hom.)
• Consequence: AMIGO3 NM_198722.3 inframe_insertion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.518

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 Benign. Variant got -7 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_198722.3
• BP6: Variant 3-49718209-C-CCAGCGGCGG is Benign according to our data. Variant chr3-49718209-C-CCAGCGGCGG is described in ClinVar as [Benign]. Clinvar id is 2653845.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMIGO3	NM_198722.3	c.1256_1257insCCGCCGCTG	p.Cys416_Arg418dup	inframe_insertion	1/1	ENST00000320431.8
RNF123	NM_022064.5	c.3500+1740_3500+1748dup		intron_variant		ENST00000327697.11
RNF123	NR_135218.2	n.3826+1740_3826+1748dup		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMIGO3	ENST00000320431.8	c.1256_1257insCCGCCGCTG	p.Cys416_Arg418dup	inframe_insertion	1/1		NM_198722.3	P1
RNF123	ENST00000327697.11	c.3500+1740_3500+1748dup		intron_variant		1	NM_022064.5	P1

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 624 AN: 152156 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00109 AC: 268 AN: 245970 Hom.: 1 AF XY: 0.000904 AC XY: 121 AN XY: 133776

Gnomad AFR exome AF: 0.0122

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000475

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.00107 AC: 1555 AN: 1460064 Hom.: 6 Cov.: 31 AF XY: 0.000983 AC XY: 714 AN XY: 726320

Gnomad4 AFR exome AF: 0.0149

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000383

Gnomad4 NFE exome AF: 0.000780

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00410 AC: 624 AN: 152272 Hom.: 2 Cov.: 33 AF XY: 0.00398 AC XY: 296 AN XY: 74452

Gnomad4 AFR AF: 0.0130

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.00331

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

AMIGO3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs543098573; hg19: chr3-49755642;