rs777468144

Positions:

• chr4-2825178-A-C
• chr4-2825178-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000503393.8(SH3BP2):​c.410A>C​(p.Asp137Ala) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D137G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH3BP2 ENST00000503393.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41

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 Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01061967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.410A>C	p.Asp137Ala	missense_variant	5/13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.581A>C	p.Asp194Ala	missense_variant	5/13		NP_001139328.1
SH3BP2	NM_001145855.2	c.494A>C	p.Asp165Ala	missense_variant	5/13		NP_001139327.1
SH3BP2	NM_003023.4	c.410A>C	p.Asp137Ala	missense_variant	5/13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.410A>C	p.Asp137Ala	missense_variant	5/13	1	NM_001122681.2	ENSP00000422168	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 151868 Hom.: 0 Cov.: 34 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000427 AC: 61 AN: 1429466 Hom.: 0 Cov.: 32 AF XY: 0.0000353 AC XY: 25 AN XY: 708216

Gnomad4 AFR exome AF: 0.000308

Gnomad4 AMR exome AF: 0.000551

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.000106

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.000118

Gnomad4 NFE exome AF: 0.0000155

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000658 AC: 1 AN: 151868 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74156

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000642 AC: 77

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;.;.;T;T;.;.;T;T;.;T
Eigen	Benign	-0.078
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	.;.;T;T;T;T;T;.;.;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.011	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.2	L;.;.;.;.;.;.;L;L;.;L
MutationTaster	Benign	0.97	D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.060	T;D;D;D;D;T;D;T;T;T;T
Polyphen		0.19	B;.;.;.;.;.;.;B;B;.;B
Vest4		0.17
MVP		0.89
MPC		0.23
ClinPred		0.031	T
GERP RS		5.2
Varity_R		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs777468144; hg19: chr4-2826905;