rs755387801

Variant names:

• chr4-2827661-C-A
• rs755387801
• NM_001122681.2:c.573C>A

Your query was ambiguous. Multiple possible variants found:

• chr4-2827661-C-A
• chr4-2827661-C-G
• chr4-2827661-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001122681.2(SH3BP2):​c.573C>A​(p.Pro191Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000835 in 1,197,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P191P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: SH3BP2 NM_001122681.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.57
• 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), G2P, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=-2.57 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.573C>A	p.Pro191Pro	synonymous_variant	Exon 7 of 13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.744C>A	p.Pro248Pro	synonymous_variant	Exon 7 of 13		NP_001139328.1
SH3BP2	NM_001145855.2	c.657C>A	p.Pro219Pro	synonymous_variant	Exon 7 of 13		NP_001139327.1
SH3BP2	NM_003023.4	c.573C>A	p.Pro191Pro	synonymous_variant	Exon 7 of 13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.573C>A	p.Pro191Pro	synonymous_variant	Exon 7 of 13	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 8.35e-7 AC: 1 AN: 1197218 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 595822

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000342 AC: 1 AN: 29250

American (AMR) AF: 0.00 AC: 0 AN: 37450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19216

East Asian (EAS) AF: 0.00 AC: 0 AN: 24890

South Asian (SAS) AF: 0.00 AC: 0 AN: 79822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4814

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 918156

Other (OTH) AF: 0.00 AC: 0 AN: 46662

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.3
DANN	Benign	0.56
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Other links and lift over

dbSNP: rs755387801; hg19: chr4-2829388;