rs121909149

chr4-2831573-G-Achr4-2831573-G-Cchr4-2831573-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_001122681.2(SH3BP2):c.1244G>A(p.Arg415Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,427,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R415P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SH3BP2 NM_001122681.2 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.78

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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001122681.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-2831573-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 7550.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821
• PP5: Variant 4-2831573-G-A is Pathogenic according to our data. Variant chr4-2831573-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.1244G>A	p.Arg415Gln	missense_variant, splice_region_variant	9/13	ENST00000503393.8
SH3BP2	NM_001145856.2	c.1415G>A	p.Arg472Gln	missense_variant, splice_region_variant	9/13
SH3BP2	NM_001145855.2	c.1328G>A	p.Arg443Gln	missense_variant, splice_region_variant	9/13
SH3BP2	NM_003023.4	c.1244G>A	p.Arg415Gln	missense_variant, splice_region_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1244G>A	p.Arg415Gln	missense_variant, splice_region_variant	9/13	1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1427572 Hom.: 0 Cov.: 32 AF XY: 0.00000283 AC XY: 2 AN XY: 707110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 16, 2023	ClinVar contains an entry for this variant (Variation ID: 7551). This missense change has been observed in individual(s) with cherubism (PMID: 11381256, 21045962, 22795151, 24382142, 24608212, 26064398, 28644570, 30236129). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 415 of the SH3BP2 protein (p.Arg415Gln). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SH3BP2 function (PMID: 16786512, 22153077). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

SH3BP2: PM1:Strong, PM2, PM5, PS4:Moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D;.;D;D;.;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.013	D;D;D;D;D;D
Sift4G	Benign	0.27	T;T;T;T;T;T
Polyphen		0.99	D;.;D;D;.;D
Vest4		0.59
MVP		0.96
MPC		0.46
ClinPred		0.95	D
GERP RS		5.7
Varity_R		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121909149; hg19: chr4-2833300;