2-109129632-G-T

Variant names:

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

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>T​(p.Arg31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,341,212 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SH3RF3 NM_001099289.3 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.13577026).

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>T	p.Arg31Leu	missense	Exon 1 of 10	NP_001092759.1	Q8TEJ3
	SH3RF3-AS1	NR_029193.1		n.488C>A		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>T	p.Arg31Leu	missense	Exon 1 of 10	ENSP00000309186.6	Q8TEJ3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1341212 Hom.: 0 Cov.: 33 AF XY: 0.00000303 AC XY: 2 AN XY: 660798

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

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 4300

European-Non Finnish (NFE) AF: 0.00000188 AC: 2 AN: 1061852

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.47	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.96
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.035
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.023	D
Polyphen		0.078	B
Vest4		0.21
MutPred		0.25		Gain of methylation at R34 (P = 0.0528)
MVP		0.068
MPC		0.24
ClinPred		0.32	T
GERP RS		0.86
PromoterAI		-0.025	Neutral
Varity_R		0.11
gMVP		0.43
Mutation Taster		=90/10	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;