4-2827682-G-T

Variant names:

• chr4-2827682-G-T
• rs28516876
• NM_001122681.2:c.586+8G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001122681.2(SH3BP2):​c.586+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH3BP2 NM_001122681.2 splice_region, intron
• Scores: Splicing: ADA: 0.0005681
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• 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), Orphanet, G2P, PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	NM_001122681.2	MANE Select	c.586+8G>T		splice_region intron	N/A	NP_001116153.1	A0A384N6E5
	SH3BP2	NM_001145856.2		c.757+8G>T		splice_region intron	N/A	NP_001139328.1	P78314-4
	SH3BP2	NM_001145855.2		c.670+8G>T		splice_region intron	N/A	NP_001139327.1	P78314-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.586+8G>T		splice_region intron	N/A	ENSP00000422168.3	P78314-1
	SH3BP2	ENST00000511747.6	TSL:1	c.757+8G>T		splice_region intron	N/A	ENSP00000424846.2	P78314-4
	SH3BP2	ENST00000356331.10	TSL:1	n.847+8G>T		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1417120 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 701516

African (AFR) AF: 0.00 AC: 0 AN: 32668

American (AMR) AF: 0.00 AC: 0 AN: 38978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25358

East Asian (EAS) AF: 0.00 AC: 0 AN: 37806

South Asian (SAS) AF: 0.00 AC: 0 AN: 81064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086246

Other (OTH) AF: 0.00 AC: 0 AN: 58664

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.5
DANN	Benign	0.59
PhyloP100		1.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00057
dbscSNV1_RF	Benign	0.024
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

Other links and lift over

dbSNP: rs28516876; hg19: chr4-2829409;