chr4-2831573-G-A

Variant names:

• chr4-2831573-G-A
• rs121909149
• NM_001122681.2:c.1244G>A

Variant summary

Our verdict is Pathogenic. The variant received 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R415L) has been classified as Uncertain significance.

• 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:4
• Conservation: PhyloP100: 7.78
• Publications: 19 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), G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 VariationId is 7550.Status of the report is criteria_provided_single_submitter, 1 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 VariationId is 7551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.1244G>A	p.Arg415Gln	missense_variant, splice_region_variant	Exon 9 of 13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.1415G>A	p.Arg472Gln	missense_variant, splice_region_variant	Exon 9 of 13		NP_001139328.1
SH3BP2	NM_001145855.2	c.1328G>A	p.Arg443Gln	missense_variant, splice_region_variant	Exon 9 of 13		NP_001139327.1
SH3BP2	NM_003023.4	c.1244G>A	p.Arg415Gln	missense_variant, splice_region_variant	Exon 9 of 13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1244G>A	p.Arg415Gln	missense_variant, splice_region_variant	Exon 9 of 13	1	NM_001122681.2	ENSP00000422168.3

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

African (AFR) AF: 0.00 AC: 0 AN: 32572

American (AMR) AF: 0.00 AC: 0 AN: 40568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25546

East Asian (EAS) AF: 0.00 AC: 0 AN: 37690

South Asian (SAS) AF: 0.00 AC: 0 AN: 81914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1093974

Other (OTH) AF: 0.00 AC: 0 AN: 59032

GnomAD4 genome Cov.: 32

Alfa AF: 0.000945 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Pathogenic:3

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 7551). 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. Experimental studies have shown that this missense change affects SH3BP2 function (PMID: 16786512, 22153077). For these reasons, this variant has been classified as Pathogenic. -

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Uncertain	0.91	.;D;.;.;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
PhyloP100		7.8
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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121909149; hg19: chr4-2833300;