rs121909148

chr4-2831582-C-Achr4-2831582-C-Gchr4-2831582-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_001122681.2(SH3BP2):c.1253C>A(p.Pro418His) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,435,998 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. P418L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SH3BP2 NM_001122681.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.68

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 Likely_pathogenic. Variant got 9 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 chr4-2831582-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814
• PP5: Variant 4-2831582-C-A is Pathogenic according to our data. Variant chr4-2831582-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 7549.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.1253C>A	p.Pro418His	missense_variant	9/13	ENST00000503393.8
SH3BP2	NM_001145856.2	c.1424C>A	p.Pro475His	missense_variant	9/13
SH3BP2	NM_001145855.2	c.1337C>A	p.Pro446His	missense_variant	9/13
SH3BP2	NM_003023.4	c.1253C>A	p.Pro418His	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1253C>A	p.Pro418His	missense_variant	9/13	1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435998 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 711922

Gnomad4 AFR exome AF: 0.0000305

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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	May 05, 2022	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 418 of the SH3BP2 protein (p.Pro418His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cherubism (PMID: 11381256, 28644570). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7549). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects SH3BP2 function (PMID: 15507112, 21794028, 22153076, 22153077). This variant disrupts the p.Pro418 amino acid residue in SH3BP2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17321449, 23298620, 28644570). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;D;D;.;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;D
Vest4		0.60
MutPred		0.51		Loss of catalytic residue at P417 (P = 0.016);.;Loss of catalytic residue at P417 (P = 0.016);Loss of catalytic residue at P417 (P = 0.016);.;Loss of catalytic residue at P417 (P = 0.016);
MVP		0.97
MPC		0.74
ClinPred		0.97	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.83

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: rs121909146; hg19: chr4-2833309;