Genetic Variant SH3RF3:p.Ala145Val (chr2-109129974-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001099289.3(SH3RF3):c.434C>T(p.Ala145Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,174,576 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: not found (cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SH3RF3
NM_001099289.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.885

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

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=0.100794286).

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.434C>T	p.Ala145Val	missense	Exon 1 of 10	NP_001092759.1	Q8TEJ3
	SH3RF3-AS1	NR_029193.1		n.146G>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.434C>T	p.Ala145Val	missense	Exon 1 of 10	ENSP00000309186.6	Q8TEJ3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

6072

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000187

AC:

AN:

1174576

Hom.:

Cov.:

AF XY:

0.0000211

AC XY:

AN XY:

568596

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23480

American (AMR)

AF:

0.00

AC:

AN:

9536

Ashkenazi Jewish (ASJ)

AF:

0.000562

AC:

AN:

16016

East Asian (EAS)

AF:

0.00

AC:

AN:

26858

South Asian (SAS)

AF:

0.00

AC:

AN:

44094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3238

European-Non Finnish (NFE)

AF:

0.0000133

AC:

AN:

975892

Other (OTH)

AF:

0.00

AC:

AN:

47650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.00088

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.41

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.1

PhyloP100

0.89

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.42

REVEL

Benign

0.033

Sift

Benign

0.37

Sift4G

Benign

0.39

Polyphen

0.18

Vest4

0.034

MutPred

0.27

Loss of glycosylation at P147 (P = 0.133)

MVP

0.26

MPC

0.19

ClinPred

0.19

GERP RS

2.7

Varity_R

0.028

gMVP

0.31

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over