4-2831588-G-C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_001122681.2(SH3BP2):​c.1259G>C​(p.Gly420Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G420R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH3BP2 NM_001122681.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.00
• Publications: 0 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: Likely_pathogenic. The variant received 7 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 chr4-2831587-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 7552.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 4-2831588-G-C is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.1259G>C	p.Gly420Ala	missense_variant	Exon 9 of 13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.1430G>C	p.Gly477Ala	missense_variant	Exon 9 of 13		NP_001139328.1
SH3BP2	NM_001145855.2	c.1343G>C	p.Gly448Ala	missense_variant	Exon 9 of 13		NP_001139327.1
SH3BP2	NM_003023.4	c.1259G>C	p.Gly420Ala	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>C	p.Gly420Ala	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

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Fibrous dysplasia of jaw Pathogenic:1

Dec 11, 2021

Gemeinschaftspraxis fuer Humangenetik Dresden

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The Gly420Ala is not reported in HGMD 2021.3, gnomAD (v2.1.1), dbSNP (v151) or LOVD. On same position the pathogenic mutations Gly420Arg and Gly420Glu for the phenotype cherubism are known. In functional studies for the mutation p.Gly420Glu is shown, that it is inside an eight aminoacid motif, which is essential for recognition of SH3BP by tankyrase. Most detected mutations lay inside this motifs RSPPDGQS (AA 415-422). Multiple lines of computational evidence support a deleterious effect on the gene (AGVGD, SIFT, MutationTaster2021, Polyphen-2). In summary, the Gly420Ala variant meets our criteria to be classified as likely pathogenic. ACMG: PM1, PM2, PM5, PP3 (ACMG Guidelines, 2015)

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;D;D;.;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.0	.;D;.;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	0.0	.;.;.;.;.;.
PhyloP100		5.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.5	D;D;D;D;N;D
REVEL	Pathogenic	0.76
Sift	Benign	0.044	D;D;D;D;D;D
Sift4G	Benign	0.086	T;T;T;T;T;T
Vest4		0.38
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs28938171; hg19: chr4-2833315;