4-2832353-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001122681.2(SH3BP2):c.1429C>T(p.Arg477Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00452 in 1,613,938 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R477Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (32 hom.)
• Consequence: SH3BP2 NM_001122681.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.929

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009694606).
• BP6: Variant 4-2832353-C-T is Benign according to our data. Variant chr4-2832353-C-T is described in ClinVar as [Benign]. Clinvar id is 348592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-2832353-C-T is described in Lovd as [Likely_benign]. Variant chr4-2832353-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00304 (463/152298) while in subpopulation SAS AF= 0.0135 (65/4826). AF 95% confidence interval is 0.0108. There are 2 homozygotes in gnomad4. There are 201 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 466 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.1429C>T	p.Arg477Trp	missense_variant	11/13	ENST00000503393.8
SH3BP2	NM_001145856.2	c.1600C>T	p.Arg534Trp	missense_variant	11/13
SH3BP2	NM_001145855.2	c.1513C>T	p.Arg505Trp	missense_variant	11/13
SH3BP2	NM_003023.4	c.1429C>T	p.Arg477Trp	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1429C>T	p.Arg477Trp	missense_variant	11/13	1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes AF: 0.00306 AC: 466 AN: 152180 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00476

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00455 AC: 1143 AN: 251430 Hom.: 7 AF XY: 0.00525 AC XY: 713 AN XY: 135906

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00130

Gnomad SAS exome AF: 0.0147

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00492

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00467 AC: 6824 AN: 1461640 Hom.: 32 Cov.: 32 AF XY: 0.00505 AC XY: 3675 AN XY: 727134

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00459

Gnomad4 OTH exome AF: 0.00416

GnomAD4 genome AF: 0.00304 AC: 463 AN: 152298 Hom.: 2 Cov.: 32 AF XY: 0.00270 AC XY: 201 AN XY: 74464

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00173

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00476

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00462 Hom.: 1

Bravo AF: 0.00286

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00476 AC: 578

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00665

EpiControl AF: 0.00563

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

-

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;D;D;.;D
Eigen	Benign	0.069
Eigen_PC	Benign	0.014
FATHMM_MKL	Benign	0.37	N
MetaRNN	Benign	0.0097	T;T;T;T;T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D;D;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D
Polyphen		0.99	D;.;D;D;.;D
Vest4		0.44
MVP		0.89
MPC		0.50
ClinPred		0.030	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066

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

Publications

LitVar

Other links and lift over

dbSNP: rs148761331; hg19: chr4-2834080;