4-2831573-G-C

Position:

• chr4-2831573-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001122681.2(SH3BP2):​c.1244G>C​(p.Arg415Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH3BP2 NM_001122681.2 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.78

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 4-2831573-G-C is Pathogenic according to our data. Variant chr4-2831573-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 7550.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.1244G>C	p.Arg415Pro	missense_variant, splice_region_variant	9/13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.1415G>C	p.Arg472Pro	missense_variant, splice_region_variant	9/13		NP_001139328.1
SH3BP2	NM_001145855.2	c.1328G>C	p.Arg443Pro	missense_variant, splice_region_variant	9/13		NP_001139327.1
SH3BP2	NM_003023.4	c.1244G>C	p.Arg415Pro	missense_variant, splice_region_variant	9/13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1244G>C	p.Arg415Pro	missense_variant, splice_region_variant	9/13	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Fibrous dysplasia of jaw Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 16, 2024	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 415 of the SH3BP2 protein (p.Arg415Pro). 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, 28721660). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7550). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SH3BP2 function (PMID: 22153077). This variant disrupts the p.Arg415 amino acid residue in SH3BP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11381256, 21045962, 22795151, 24382142, 24608212, 26064398, 28644570; 30236129)). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;D;D;.;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;.;.;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0060	D;D;D;D;D;D
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		0.99	D;.;D;D;.;D
Vest4		0.71
MutPred		0.84		Gain of glycosylation at R415 (P = 0.0237);.;Gain of glycosylation at R415 (P = 0.0237);Gain of glycosylation at R415 (P = 0.0237);.;Gain of glycosylation at R415 (P = 0.0237);
MVP		0.97
MPC		0.79
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121909149; hg19: chr4-2833300;