Genetic Variant SH3RF2:p.Arg48Gly (chr5-145938070-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_152550.4(SH3RF2):c.142C>G(p.Arg48Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R48W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SH3RF2
NM_152550.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.453

Variant links:

Genes affected

SH3RF2 (HGNC:26299): (SH3 domain containing ring finger 2) Enables protein phosphatase 1 binding activity and ubiquitin protein ligase activity. Involved in several processes, including positive regulation of JNK cascade; protein autoubiquitination; and regulation of cellular protein metabolic process. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SH3RF2 links:

LOC107986458 (HGNC:):

LOC107986458 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3RF2	NM_152550.4 link	c.142C>G	p.Arg48Gly	missense_variant	Exon 2 of 10	ENST00000359120.9	NP_689763.4	Q8TEC5-1Q08AM8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SH3RF2	ENST00000359120.9 link	c.142C>G	p.Arg48Gly	missense_variant	Exon 2 of 10	1	NM_152550.4	ENSP00000352028.4	Q8TEC5-1
SH3RF2	ENST00000511217.1 link	c.142C>G	p.Arg48Gly	missense_variant	Exon 1 of 10	1		ENSP00000424497.1	Q8TEC5-1
SH3RF2	ENST00000506591.1 link	n.*139C>G		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

0.074

Eigen_PC

Benign

-0.0047

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.93

.;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Uncertain

2.5

M;M

PhyloP100

0.45

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-6.5

D;D

REVEL

Uncertain

0.63

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.80

MutPred

0.61

Gain of ubiquitination at K45 (P = 0.1047);Gain of ubiquitination at K45 (P = 0.1047);

MVP

0.87

MPC

0.64

ClinPred

1.0

GERP RS

-0.83

PromoterAI

-0.030

Neutral

(source)

Varity_R

0.82

gMVP

0.74

Mutation Taster

=90/10

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

Loading publications...

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over