rs28938170

Positions:

• chr4-2831587-G-A
• chr4-2831587-G-C

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000503393.8(SH3BP2):​c.1258G>A​(p.Gly420Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G420A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH3BP2 ENST00000503393.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.23

Genes affected

SH3BP2 (HGNC:10825): (SH3 domain binding protein 2) The protein encoded by this gene has an N-terminal pleckstrin homology (PH) domain, an SH3-binding proline-rich region, and a C-terminal SH2 domain. The protein binds to the SH3 domains of several proteins including the ABL1 and SYK protein tyrosine kinases , and functions as a cytoplasmic adaptor protein to positively regulate transcriptional activity in T, natural killer (NK), and basophilic cells. Mutations in this gene result in cherubism. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PS1: Transcript ENST00000503393.8 (SH3BP2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 7552
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000503393.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-2831588-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1526420.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 4-2831587-G-A is Pathogenic according to our data. Variant chr4-2831587-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 372503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.1258G>A	p.Gly420Arg	missense_variant	9/13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.1429G>A	p.Gly477Arg	missense_variant	9/13		NP_001139328.1
SH3BP2	NM_001145855.2	c.1342G>A	p.Gly448Arg	missense_variant	9/13		NP_001139327.1
SH3BP2	NM_003023.4	c.1258G>A	p.Gly420Arg	missense_variant	9/13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1258G>A	p.Gly420Arg	missense_variant	9/13	1	NM_001122681.2	ENSP00000422168	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 08, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SH3BP2 function (PMID: 22153076). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 372503). This variant is also known as p.G418R. This missense change has been observed in individual(s) with cherubism (PMID: 12900899, 23298620). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 420 of the SH3BP2 protein (p.Gly420Arg). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 14, 2016

The G420R variant has been published previously in association with cherubism in an Italian family (Lo et al., 2003). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. G420R is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Another nucelotide change leading to the same amino acid change (c.1258 G>C), a missense change at the same residue (G420E), and missense variants in nearby residues (R415Q/P, P418T/H/L/R, D419N/G/Y) have been reported in the Human Gene Mutation Database in association with cherubism (Stenson et al., 2014), supporting the functional importance of this region of the protein. Furthermore, functional studies have shown that the G420R inhibits the binding of tankyrase to ARC4 ( Guettler et al., 2011). Therefore, we consider G420R a pathogenic variant. -

SH3BP2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2024

The SH3BP2 c.1258G>A variant is predicted to result in the amino acid substitution p.Gly420Arg. This variant was reported to segregate with cherubism in family with several affected individuals (Lo et al. 2003. PubMed ID: 12900899). The Gly420 residue resides in a highly conserved 8 amino acid TNKS-binding motif responsible for interactions with the ARC4 region of the TNKS2 protein and functional studies found that disruption of Gly420 results in defective binding (Guettler et al. 2011. PubMed ID: 22153077). This variant has not been reported in a large population database, indicating this variant is rare. Additionally, alternate nucleotide substitutions (c.1258G>C) which result in the same missense variant (p.Gly420Arg) have been reported in individuals with cherubism (Ueki et al. 2001. PubMed ID: 11381256). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	D;.;D;D;.;D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;.;.;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0060	D;D;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		1.0	D;.;D;D;.;D
Vest4		0.77
MutPred		0.89		Loss of sheet (P = 0.0142);.;Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);.;Loss of sheet (P = 0.0142);
MVP		0.97
MPC		0.74
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs28938170; hg19: chr4-2833314;