Genetic Variant SH3RF1:p.Arg833Gly (chr4-169106848-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_020870.4(SH3RF1):c.2497A>G(p.Arg833Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000717 in 1,395,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

SH3RF1
NM_020870.4 missense, splice_region

Scores

Splicing: ADA: 0.9858

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.47

Publications

0 publications found

Variant links:

Genes affected

SH3RF1 (HGNC:17650): (SH3 domain containing ring finger 1) This gene encodes a protein containing an N-terminus RING-finger, four SH3 domains, and a region implicated in binding of the Rho GTPase Rac. Via the RING-finger, the encoded protein has been shown to function as an ubiquitin-protein ligase involved in protein sorting at the trans-Golgi network. The encoded protein may also act as a scaffold for the c-Jun N-terminal kinase signaling pathway, facilitating the formation of a functional signaling module. [provided by RefSeq, Jul 2008]

SH3RF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020870.4. 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
	SH3RF1	NM_020870.4	MANE Select	c.2497A>G	p.Arg833Gly	missense splice_region	Exon 11 of 12	NP_065921.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3RF1	ENST00000284637.14	TSL:1 MANE Select	c.2497A>G	p.Arg833Gly	missense splice_region	Exon 11 of 12	ENSP00000284637.9	Q7Z6J0-1
SH3RF1	ENST00000924372.1		c.2557A>G	p.Arg853Gly	missense splice_region	Exon 12 of 13	ENSP00000594431.1
SH3RF1	ENST00000871180.1		c.2386A>G	p.Arg796Gly	missense splice_region	Exon 10 of 11	ENSP00000541239.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1395522

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31010

American (AMR)

AF:

0.00

AC:

AN:

33014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23112

East Asian (EAS)

AF:

0.00

AC:

AN:

38578

South Asian (SAS)

AF:

0.00

AC:

AN:

78282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5476

European-Non Finnish (NFE)

AF:

9.28e-7

AC:

AN:

1077788

Other (OTH)

AF:

0.00

AC:

AN:

57266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

PhyloP100

5.5

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.9

REVEL

Uncertain

0.39

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.92

MutPred

0.63

Loss of stability (P = 0.0348)

MVP

0.60

MPC

1.2

ClinPred

0.98

GERP RS

5.9

Varity_R

0.72

gMVP

0.82

Mutation Taster

=39/61

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over