4-2833015-C-G

Position:

• chr4-2833015-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001122681.2(SH3BP2):​c.1514C>G​(p.Ser505Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000542 in 1,614,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: SH3BP2 NM_001122681.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.934

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006813228).
• BP6: Variant 4-2833015-C-G is Benign according to our data. Variant chr4-2833015-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 348593.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}. Variant chr4-2833015-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00275 (419/152374) while in subpopulation AFR AF= 0.0088 (366/41584). AF 95% confidence interval is 0.00806. There are 0 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 419 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.1514C>G	p.Ser505Cys	missense_variant	12/13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.1685C>G	p.Ser562Cys	missense_variant	12/13		NP_001139328.1
SH3BP2	NM_001145855.2	c.1598C>G	p.Ser533Cys	missense_variant	12/13		NP_001139327.1
SH3BP2	NM_003023.4	c.1514C>G	p.Ser505Cys	missense_variant	12/13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1514C>G	p.Ser505Cys	missense_variant	12/13	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 419 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00883

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000668 AC: 168 AN: 251438 Hom.: 1 AF XY: 0.000508 AC XY: 69 AN XY: 135916

Gnomad AFR exome AF: 0.00757

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000312 AC: 456 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.000264 AC XY: 192 AN XY: 727242

Gnomad4 AFR exome AF: 0.00983

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.00275 AC: 419 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.00247 AC XY: 184 AN XY: 74514

Gnomad4 AFR AF: 0.00880

Gnomad4 AMR AF: 0.00274

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000148 Hom.: 0

Bravo AF: 0.00306

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000667 AC: 81

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fibrous dysplasia of jaw Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	SH3BP2 NM_003023 exon 12 p.Ser505Cys (c.1514C>G): This variant has not been reported in the literature but is present in 0.8% (194/24030) of African alleles, including 1 homozygote in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs144577122). This variant is present in ClinVar (Variation ID:348593). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.47	T;.;T;T;.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.79	.;T;.;.;T;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.0068	T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.050	D;D;D;D;D;D
Sift4G	Benign	0.13	T;T;T;T;T;T
Polyphen		0.69	P;.;P;P;.;P
Vest4		0.21
MVP		0.89
MPC		0.16
ClinPred		0.015	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.052

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: rs144577122; hg19: chr4-2834742;