rs35313240

Positions:

• chr4-2827265-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.464C>T​(p.Ala155Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,614,226 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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. A155T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0070 (54 hom.)
• Consequence: SH3BP2 NM_001122681.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.25

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=0.006905973).
• BP6: Variant 4-2827265-C-T is Benign according to our data. Variant chr4-2827265-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 348574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-2827265-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00442 (674/152362) while in subpopulation NFE AF= 0.00753 (512/68038). AF 95% confidence interval is 0.00699. There are 4 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 674 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.464C>T	p.Ala155Val	missense_variant	6/13	ENST00000503393.8
SH3BP2	NM_001145856.2	c.635C>T	p.Ala212Val	missense_variant	6/13
SH3BP2	NM_001145855.2	c.548C>T	p.Ala183Val	missense_variant	6/13
SH3BP2	NM_003023.4	c.464C>T	p.Ala155Val	missense_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.464C>T	p.Ala155Val	missense_variant	6/13	1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 674 AN: 152244 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00752

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00532 AC: 1337 AN: 251428 Hom.: 7 AF XY: 0.00533 AC XY: 724 AN XY: 135876

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00896

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00702 AC: 10267 AN: 1461864 Hom.: 54 Cov.: 32 AF XY: 0.00698 AC XY: 5078 AN XY: 727236

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00302

Gnomad4 ASJ exome AF: 0.00509

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00246

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.00829

Gnomad4 OTH exome AF: 0.00636

GnomAD4 genome AF: 0.00442 AC: 674 AN: 152362 Hom.: 4 Cov.: 33 AF XY: 0.00397 AC XY: 296 AN XY: 74506

Gnomad4 AFR AF: 0.00135

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00753

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00765 Hom.: 9

Bravo AF: 0.00456

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00562 AC: 682

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00851

EpiControl AF: 0.00925

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SH3BP2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;.;T;T;.;T;T;.;T
Eigen	Benign	-0.069
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.85	D
MetaRNN	Benign	0.0069	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.9	L;.;.;.;.;L;L;.;L
MutationTaster	Benign	0.57	D;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.092
Sift	Uncertain	0.0090	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.18	T;D;D;D;T;T;T;T;T
Polyphen		0.46	P;.;.;.;.;P;P;.;P
Vest4		0.21
MVP		0.90
MPC		0.18
ClinPred		0.011	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064

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: rs35313240; hg19: chr4-2828992; COSMIC: COSV100696908; COSMIC: COSV100696908;