2-109129578-C-G

Variant names:

• chr2-109129578-C-G
• rs1024924304
• NM_001099289.3:c.38C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001099289.3(SH3RF3):​c.38C>G​(p.Ala13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000003 in 1,332,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 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. A13V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: SH3RF3 NM_001099289.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15285888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3RF3	NM_001099289.3	c.38C>G	p.Ala13Gly	missense_variant	Exon 1 of 10	ENST00000309415.8	NP_001092759.1
SH3RF3	XM_011511109.3	c.38C>G	p.Ala13Gly	missense_variant	Exon 1 of 9		XP_011509411.1
RANBP2	XM_047445367.1	c.8370+356532C>G		intron_variant	Intron 24 of 24		XP_047301323.1
SH3RF3-AS1	NR_029193.1	n.542G>C		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3RF3	ENST00000309415.8	c.38C>G	p.Ala13Gly	missense_variant	Exon 1 of 10	5	NM_001099289.3	ENSP00000309186.6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000360 AC: 3 AN: 83376 Hom.: 0 AF XY: 0.0000211 AC XY: 1 AN XY: 47480

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000192

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000300 AC: 4 AN: 1332432 Hom.: 0 Cov.: 32 AF XY: 0.00000152 AC XY: 1 AN XY: 656868

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0014	T
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.086
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.48	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.035
Sift	Benign	0.17	T
Sift4G	Benign	0.30	T
Polyphen		0.70	P
Vest4		0.14
MutPred		0.25		Gain of glycosylation at K12 (P = 0.0933);
MVP		0.32
MPC		0.20
ClinPred		0.22	T
GERP RS		2.3
Varity_R		0.099
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs1024924304; hg19: chr2-109746034;