rs28938170

Variant names:

• chr4-2831587-G-A
• rs28938170
• NM_001122681.2:c.1258G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-2831587-G-A
• chr4-2831587-G-C
• chr4-2831587-G-T

Variant summary

Our verdict is Pathogenic. The variant received 26 ACMG points: 26P and 0B. PS1 PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001122681.2(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 (★★). ClinVar reports functional evidence for this variant: "SCV000490795: Furthermore, functional studies have shown that the G420R inhibits the binding of tankyrase to ARC4 (Guettler et al., 2011)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in 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 NM_001122681.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.23
• Publications: 6 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), Orphanet, G2P, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 26 ACMG points.

• PS1: Transcript NM_001122681.2 (SH3BP2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000490795: Furthermore, functional studies have shown that the G420R inhibits the binding of tankyrase to ARC4 (Guettler et al., 2011).; SCV003525488: Experimental studies have shown that this missense change affects SH3BP2 function (PMID: 22153076).; SCV005336574: Functional studies found that disruption of Gly420 results in defective binding (Guettler et al. 2011. PubMed ID: 22153077).
• 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, 0.969
• PP5: Variant 4-2831587-G-A is Pathogenic according to our data. Variant chr4-2831587-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 372503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	NM_001122681.2	MANE Select	c.1258G>A	p.Gly420Arg	missense	Exon 9 of 13	NP_001116153.1	A0A384N6E5
	SH3BP2	NM_001145856.2		c.1429G>A	p.Gly477Arg	missense	Exon 9 of 13	NP_001139328.1	P78314-4
	SH3BP2	NM_001145855.2		c.1342G>A	p.Gly448Arg	missense	Exon 9 of 13	NP_001139327.1	P78314-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.1258G>A	p.Gly420Arg	missense	Exon 9 of 13	ENSP00000422168.3	P78314-1
	SH3BP2	ENST00000511747.6	TSL:1	c.1429G>A	p.Gly477Arg	missense	Exon 9 of 13	ENSP00000424846.2	P78314-4
	SH3BP2	ENST00000356331.10	TSL:1	n.1519G>A		non_coding_transcript_exon	Exon 9 of 13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Fibrous dysplasia of jaw (1)
1	-	-	not provided (1)
1	-	-	SH3BP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.97	D
PhyloP100		6.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.77
MutPred		0.89		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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs28938170; hg19: chr4-2833314;