NM_001122681.2:c.1259G>A

Variant names:

• chr4-2831588-G-A
• rs28938171
• NM_001122681.2:c.1259G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001122681.2(SH3BP2):​c.1259G>A​(p.Gly420Glu) 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 Uncertain significance (★). 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 NM_001122681.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.00
• Publications: 9 publications found

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]

SH3BP2 Gene-Disease associations (from GenCC):

• cherubism

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001122681.2
• 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 VariationId is 1526420.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.1259G>A	p.Gly420Glu	missense_variant	Exon 9 of 13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.1430G>A	p.Gly477Glu	missense_variant	Exon 9 of 13		NP_001139328.1
SH3BP2	NM_001145855.2	c.1343G>A	p.Gly448Glu	missense_variant	Exon 9 of 13		NP_001139327.1
SH3BP2	NM_003023.4	c.1259G>A	p.Gly420Glu	missense_variant	Exon 9 of 13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1259G>A	p.Gly420Glu	missense_variant	Exon 9 of 13	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000717 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fibrous dysplasia of jaw Pathogenic:1 Uncertain:1

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 420 of the SH3BP2 protein (p.Gly420Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cherubism (PMID: 11381256, 19576004). ClinVar contains an entry for this variant (Variation ID: 7553). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SH3BP2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Gly420 amino acid residue in SH3BP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12900899, 23298620). 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: 16786512, 22153077). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;D;D;.;D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;.;.;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
PhyloP100		5.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0070	D;D;D;D;D;D
Sift4G	Benign	0.087	T;T;T;T;T;T
Polyphen		1.0	D;.;D;D;.;D
Vest4		0.71
MutPred		0.86		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		0.77
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28938171; hg19: chr4-2833315;