rs11893469

Variant names:

• chr2-109190687-C-T
• rs11893469
• NM_001099289.3:c.573+60574C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001099289.3(SH3RF3):​c.573+60574C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 151,992 control chromosomes in the GnomAD database, including 1,470 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1470 hom., cov: 32)
• Consequence: SH3RF3 NM_001099289.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.901
• Publications: 9 publications found

Genes affected

SH3RF3 (HGNC:24699): (SH3 domain containing ring finger 3) Enables ubiquitin protein ligase activity. Involved in positive regulation of JNK cascade and protein autoubiquitination. [provided by Alliance of Genome Resources, Apr 2022]

RANBP2 (HGNC:9848): (RAN binding protein 2) RAN is a small GTP-binding protein of the RAS superfamily that is associated with the nuclear membrane and is thought to control a variety of cellular functions through its interactions with other proteins. This gene encodes a very large RAN-binding protein that immunolocalizes to the nuclear pore complex. The protein is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in the Ran-GTPase cycle. The encoded protein directly interacts with the E2 enzyme UBC9 and strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on chromosome 2q. [provided by RefSeq, Jul 2008]

RANBP2 Gene-Disease associations (from GenCC):

• familial acute necrotizing encephalopathy

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3RF3	NM_001099289.3	c.573+60574C>T		intron_variant	Intron 1 of 9	ENST00000309415.8	NP_001092759.1
RANBP2	XM_047445367.1	c.8370+417641C>T		intron_variant	Intron 24 of 24		XP_047301323.1
SH3RF3	XM_011511109.3	c.573+60574C>T		intron_variant	Intron 1 of 8		XP_011509411.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3RF3	ENST00000309415.8	c.573+60574C>T		intron_variant	Intron 1 of 9	5	NM_001099289.3	ENSP00000309186.6

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18981 AN: 151874 Hom.: 1473 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.0965

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.135

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.125 AC: 18973 AN: 151992 Hom.: 1470 Cov.: 32 AF XY: 0.128 AC XY: 9480 AN XY: 74292

African (AFR) AF: 0.0530 AC: 2200 AN: 41472

American (AMR) AF: 0.101 AC: 1542 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 444 AN: 3468

East Asian (EAS) AF: 0.108 AC: 559 AN: 5168

South Asian (SAS) AF: 0.0970 AC: 466 AN: 4804

European-Finnish (FIN) AF: 0.240 AC: 2527 AN: 10536

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10733 AN: 67962

Other (OTH) AF: 0.134 AC: 281 AN: 2104

Alfa AF: 0.141 Hom.: 910

Bravo AF: 0.112

Asia WGS AF: 0.117 AC: 405 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	10
DANN	Benign	0.44
PhyloP100		0.90

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

Other links and lift over

dbSNP: rs11893469; hg19: chr2-109807143;