2-109345888-T-C

Variant names:

• chr2-109345888-T-C
• rs6754115
• NM_001099289.3:c.574-1786T>C

Variant summary

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

The NM_001099289.3(SH3RF3):​c.574-1786T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.692 in 152,102 control chromosomes in the GnomAD database, including 37,647 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 0.69 (37647 hom., cov: 32)
• Consequence: SH3RF3 NM_001099289.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.55
• Publications: 3 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3RF3	NM_001099289.3	c.574-1786T>C		intron_variant	Intron 1 of 9	ENST00000309415.8	NP_001092759.1
RANBP2	XM_047445367.1	c.8371-495516T>C		intron_variant	Intron 24 of 24		XP_047301323.1
SH3RF3	XM_011511109.3	c.574-1786T>C		intron_variant	Intron 1 of 8		XP_011509411.1
SH3RF3	XM_047444144.1	c.-231-1786T>C		intron_variant	Intron 1 of 9		XP_047300100.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3RF3	ENST00000309415.8	c.574-1786T>C		intron_variant	Intron 1 of 9	5	NM_001099289.3	ENSP00000309186.6

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105201 AN: 151984 Hom.: 37603 Cov.: 32

Gnomad AFR AF: 0.865

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.734

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.890

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.555

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.714

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

GnomAD4 genome AF: 0.692 AC: 105303 AN: 152102 Hom.: 37647 Cov.: 32 AF XY: 0.690 AC XY: 51301 AN XY: 74340

African (AFR) AF: 0.865 AC: 35917 AN: 41516

American (AMR) AF: 0.734 AC: 11218 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 2000 AN: 3468

East Asian (EAS) AF: 0.890 AC: 4596 AN: 5166

South Asian (SAS) AF: 0.598 AC: 2878 AN: 4812

European-Finnish (FIN) AF: 0.555 AC: 5860 AN: 10560

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.599 AC: 40728 AN: 67980

Other (OTH) AF: 0.716 AC: 1510 AN: 2110

Alfa AF: 0.628 Hom.: 50556

Bravo AF: 0.717

Asia WGS AF: 0.753 AC: 2614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.1
DANN	Benign	0.72
PhyloP100		-1.6

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: rs6754115; hg19: chr2-109962344;