4-2820618-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001122681.2(SH3BP2):c.1A>G(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: SH3BP2 NM_001122681.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.68

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 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.1A>G	p.Met1?	start_lost	2/13	ENST00000503393.8
SH3BP2	NM_003023.4	c.1A>G	p.Met1?	start_lost	2/13
SH3BP2	NM_001145856.2	c.172A>G	p.Met58Val	missense_variant	2/13
SH3BP2	NM_001145855.2	c.85A>G	p.Met29Val	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1A>G	p.Met1?	start_lost	2/13	1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 34

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fibrous dysplasia of jaw Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2023

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 2414440). This variant has not been reported in the literature in individuals affected with SH3BP2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SH3BP2 mRNA. The next in-frame methionine is located at codon 6. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;.;T;T;.;.;.;T;T;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	1.0	D;D;N;N;N;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.96	D;.;.;.;.;.;.;.;D;D;.;D
Vest4		0.89
MutPred		0.78		Gain of catalytic residue at M1 (P = 0.0499);Gain of catalytic residue at M1 (P = 0.0499);Gain of catalytic residue at M1 (P = 0.0499);Gain of catalytic residue at M1 (P = 0.0499);Gain of catalytic residue at M1 (P = 0.0499);Gain of catalytic residue at M1 (P = 0.0499);.;Gain of catalytic residue at M1 (P = 0.0499);Gain of catalytic residue at M1 (P = 0.0499);Gain of catalytic residue at M1 (P = 0.0499);.;Gain of catalytic residue at M1 (P = 0.0499);
MVP		0.88
MPC		0.69
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.78

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: rs1577354982; hg19: chr4-2822345;