rs548212932

Positions:

• chr4-2832418-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001122681.2(SH3BP2):​c.1488+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000682 in 1,612,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: SH3BP2 NM_001122681.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00001263
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.07

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000854 (13/152276) while in subpopulation AMR AF= 0.000588 (9/15300). AF 95% confidence interval is 0.000307. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.1488+6C>T		splice_donor_region_variant, intron_variant		ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145855.2	c.1572+6C>T		splice_donor_region_variant, intron_variant			NP_001139327.1
SH3BP2	NM_001145856.2	c.1659+6C>T		splice_donor_region_variant, intron_variant			NP_001139328.1
SH3BP2	NM_003023.4	c.1488+6C>T		splice_donor_region_variant, intron_variant			NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1488+6C>T		splice_donor_region_variant, intron_variant		1	NM_001122681.2	ENSP00000422168	P2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000678 AC: 17 AN: 250816 Hom.: 0 AF XY: 0.0000884 AC XY: 12 AN XY: 135794

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000664 AC: 97 AN: 1460460 Hom.: 0 Cov.: 31 AF XY: 0.0000784 AC XY: 57 AN XY: 726646

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000612

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74456

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000117

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

Labcorp Genetics (formerly Invitae), Labcorp

Nov 12, 2023

This sequence change falls in intron 11 of the SH3BP2 gene. It does not directly change the encoded amino acid sequence of the SH3BP2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs548212932, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with SH3BP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 525206). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.21
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000013
dbscSNV1_RF	Benign	0.028
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: rs548212932; hg19: chr4-2834145;