NM_001099289.3:c.92G>C

Variant names:

• chr2-109129632-G-C
• rs1676633128
• NM_001099289.3:c.92G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099289.3(SH3RF3):​c.92G>C​(p.Arg31Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,493,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: SH3RF3 NM_001099289.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.965
• Publications: 0 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]

SH3RF3-AS1 (HGNC:44168): (SH3RF3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16184989).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099289.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3RF3	NM_001099289.3	MANE Select	c.92G>C	p.Arg31Pro	missense	Exon 1 of 10	NP_001092759.1	Q8TEJ3
	SH3RF3-AS1	NR_029193.1		n.488C>G		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3RF3	ENST00000309415.8	TSL:5 MANE Select	c.92G>C	p.Arg31Pro	missense	Exon 1 of 10	ENSP00000309186.6	Q8TEJ3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152064 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000261 AC: 35 AN: 1341212 Hom.: 0 Cov.: 33 AF XY: 0.0000288 AC XY: 19 AN XY: 660798

African (AFR) AF: 0.00 AC: 0 AN: 27222

American (AMR) AF: 0.0000338 AC: 1 AN: 29572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23122

East Asian (EAS) AF: 0.00 AC: 0 AN: 31346

South Asian (SAS) AF: 0.00 AC: 0 AN: 73394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34444

Middle Eastern (MID) AF: 0.000233 AC: 1 AN: 4300

European-Non Finnish (NFE) AF: 0.0000311 AC: 33 AN: 1061852

Other (OTH) AF: 0.00 AC: 0 AN: 55960

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152064 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74276

African (AFR) AF: 0.00 AC: 0 AN: 41426

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.96
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.025
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.018	D
Polyphen		0.38	B
Vest4		0.24
MutPred		0.24		Loss of helix (P = 0.0041)
MVP		0.082
MPC		0.31
ClinPred		0.39	T
GERP RS		0.86
PromoterAI		0.0014	Neutral
Varity_R		0.23
gMVP		0.46
Mutation Taster		=88/12	polymorphism

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: rs1676633128; hg19: chr2-109746088;