4-2832353-C-T

Variant names:

• chr4-2832353-C-T
• rs148761331
• NM_001122681.2:c.1429C>T

Variant summary

Our verdict is Benign. The variant received -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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.929
• Publications: 13 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: Benign. The variant received -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/Likely_benign. ClinVar VariationId is 348592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 463 AD gene.

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.1429C>T	p.Arg477Trp	missense	Exon 11 of 13	NP_001116153.1	A0A384N6E5
	SH3BP2	NM_001145856.2		c.1600C>T	p.Arg534Trp	missense	Exon 11 of 13	NP_001139328.1	P78314-4
	SH3BP2	NM_001145855.2		c.1513C>T	p.Arg505Trp	missense	Exon 11 of 13	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.1429C>T	p.Arg477Trp	missense	Exon 11 of 13	ENSP00000422168.3	P78314-1
	SH3BP2	ENST00000511747.6	TSL:1	c.1600C>T	p.Arg534Trp	missense	Exon 11 of 13	ENSP00000424846.2	P78314-4
	SH3BP2	ENST00000356331.10	TSL:1	n.1690C>T		non_coding_transcript_exon	Exon 11 of 13

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

GnomAD2 exomes AF: 0.00455 AC: 1143 AN: 251430 AF XY: 0.00525

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 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

African (AFR) AF: 0.000836 AC: 28 AN: 33476

American (AMR) AF: 0.00112 AC: 50 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00283 AC: 74 AN: 26136

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39698

South Asian (SAS) AF: 0.0141 AC: 1217 AN: 86250

European-Finnish (FIN) AF: 0.000449 AC: 24 AN: 53398

Middle Eastern (MID) AF: 0.00971 AC: 56 AN: 5768

European-Non Finnish (NFE) AF: 0.00459 AC: 5100 AN: 1111810

Other (OTH) AF: 0.00416 AC: 251 AN: 60384

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

African (AFR) AF: 0.000698 AC: 29 AN: 41552

American (AMR) AF: 0.000980 AC: 15 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5190

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00476 AC: 324 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00438 Hom.: 3

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Fibrous dysplasia of jaw (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.069
Eigen_PC	Benign	0.014
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-0.48	T
PhyloP100		0.93
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.012	D
Polyphen		0.99	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
Mutation Taster		=94/6	polymorphism

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: rs148761331; hg19: chr4-2834080;