4-2833814-G-C

Position:

• chr4-2833814-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001122681.2(SH3BP2):​c.1666G>C​(p.Gly556Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000701 in 1,427,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SH3BP2 NM_001122681.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.24

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.1666G>C	p.Gly556Arg	missense_variant	13/13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.1837G>C	p.Gly613Arg	missense_variant	13/13		NP_001139328.1
SH3BP2	NM_001145855.2	c.1750G>C	p.Gly584Arg	missense_variant	13/13		NP_001139327.1
SH3BP2	NM_003023.4	c.1666G>C	p.Gly556Arg	missense_variant	13/13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1666G>C	p.Gly556Arg	missense_variant	13/13	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427040 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 707240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D;.;D;D;.;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.89	.;D;.;.;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Uncertain	2.0	M;.;M;M;.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.5	N;N;N;N;N;N
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;D
Vest4		0.62
MutPred		0.60		Gain of MoRF binding (P = 0.0019);.;Gain of MoRF binding (P = 0.0019);Gain of MoRF binding (P = 0.0019);.;Gain of MoRF binding (P = 0.0019);
MVP		0.94
MPC		0.75
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.34

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: rs201197278; hg19: chr4-2835541;