rs121909147

Positions:

• chr4-2831582-C-G
• chr4-2831582-C-T
• chr4-2831582-C-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The ENST00000503393.8(SH3BP2):​c.1253C>G​(p.Pro418Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,435,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P418L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SH3BP2 ENST00000503393.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.68

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 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr4-2831582-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.808
• PP5: Variant 4-2831582-C-G is Pathogenic according to our data. Variant chr4-2831582-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 7548.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.1253C>G	p.Pro418Arg	missense_variant	9/13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.1424C>G	p.Pro475Arg	missense_variant	9/13		NP_001139328.1
SH3BP2	NM_001145855.2	c.1337C>G	p.Pro446Arg	missense_variant	9/13		NP_001139327.1
SH3BP2	NM_003023.4	c.1253C>G	p.Pro418Arg	missense_variant	9/13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1253C>G	p.Pro418Arg	missense_variant	9/13	1	NM_001122681.2	ENSP00000422168	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1435998 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 711922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 25, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro418 amino acid residue in SH3BP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17321449, 23298620, 28644570). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SH3BP2 function (PMID: 21794028, 22153076, 22153077, 24916406, 25144740). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SH3BP2 protein function. ClinVar contains an entry for this variant (Variation ID: 7548). This missense change has been observed in individual(s) with cherubism (PMID: 11381256, 14577811, 18596838, 30236129). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 418 of the SH3BP2 protein (p.Pro418Arg). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jul 01, 2022	This sequence change in SH3BP2 is predicted to replace proline with arginine at codon 418, p.(Pro418Arg). The proline residue is highly conserved (100 vertebrates, UCSC), and is located within the RSPPDG peptide sequence lying between the PH and SH2 domains, amino acids 415-420, which is defined as a mutational hotspot (PMID: 22640988). There is a large physicochemical difference between proline and arginine. This variant is absent from gnomAD v2.1 and v3.1. This is the most commonly reported variant in families with a clinical diagnosis of Cherubism (PMID: 11381256, 22640988, 30236129). Functional assays demonstrate that the variant causes a gain-of-function by increasing the interaction with specific signalling molecules and a homozygous Sh3bp2 Pro416Arg knock-in mouse model recapitulates the human cherubism phenotype (PMID: 17218256, 20117257, 21794028). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/5 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PS4, PM1, PM2_Supporting, PP3. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2021	Published functional studies demonstrate P418R causes gain of function by increasing interaction of B cells with specific signaling molecules (Lietman et al., 2006; Levaot et al., 2011; Ogi et al., 2011; Mukai et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22153077, 24916406, 21794028, 25144740, 16786512, 20691350, 11381256, 18596838, 14577811, 29669173, 30236129, 28904407, 22153076, 27498064) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;D;D;.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	.;D;.;.;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0060	D;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;D
Vest4		0.61
MutPred		0.47		Gain of MoRF binding (P = 0.0053);.;Gain of MoRF binding (P = 0.0053);Gain of MoRF binding (P = 0.0053);.;Gain of MoRF binding (P = 0.0053);
MVP		0.97
MPC		0.70
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80

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

Other links and lift over

dbSNP: rs121909146; hg19: chr4-2833309;