2-109129578-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001099289.3(SH3RF3):c.38C>T(p.Ala13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000269 in 1,484,436 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SH3RF3
NM_001099289.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.64

Variant links:

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]

SH3RF3 links:

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 links:

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

SH3RF3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.19347125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3RF3	NM_001099289.3 link	c.38C>T	p.Ala13Val	missense_variant	Exon 1 of 10	ENST00000309415.8	NP_001092759.1	Q8TEJ3
SH3RF3	XM_011511109.3 link	c.38C>T	p.Ala13Val	missense_variant	Exon 1 of 9		XP_011509411.1
RANBP2	XM_047445367.1 link	c.8370+356532C>T		intron_variant	Intron 24 of 24		XP_047301323.1
SH3RF3-AS1	NR_029193.1 link	n.542G>A		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 link	c.38C>T	p.Ala13Val	missense_variant	Exon 1 of 10	5	NM_001099289.3	ENSP00000309186.6		Q8TEJ3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1332430

Hom.:

Cov.:

AF XY:

0.00000304

AC XY:

AN XY:

656866

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000333

Gnomad4 SAS exome

AF:

0.0000136

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.38C>T (p.A13V) alteration is located in exon (coding exon ) of the SH3RF3 gene. This alteration results from a C to T substitution at nucleotide position 38, causing the alanine (A) at amino acid position 13 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0023

Eigen

Benign

-0.062

Eigen_PC

Benign

-0.063

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.71

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.99

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.38

REVEL

Benign

0.063

Sift

Uncertain

0.010

Sift4G

Uncertain

0.024

Polyphen

0.72

Vest4

0.22

MutPred

0.32

Gain of ubiquitination at K12 (P = 0.0737);

MVP

0.22

MPC

0.19

ClinPred

0.92

GERP RS

2.3

Varity_R

0.17

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over