chr4-2831582-C-A

Variant names:

• chr4-2831582-C-A
• rs121909146
• NM_001122681.2:c.1253C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 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. P418T) 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
• Publications: 35 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr4-2831581-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 863669.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 VariationId is 7549.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.1253C>A	p.Pro418His	missense_variant	Exon 9 of 13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.1424C>A	p.Pro475His	missense_variant	Exon 9 of 13		NP_001139328.1
SH3BP2	NM_001145855.2	c.1337C>A	p.Pro446His	missense_variant	Exon 9 of 13		NP_001139327.1
SH3BP2	NM_003023.4	c.1253C>A	p.Pro418His	missense_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.1253C>A	p.Pro418His	missense_variant	Exon 9 of 13	1	NM_001122681.2	ENSP00000422168.3

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

African (AFR) AF: 0.0000305 AC: 1 AN: 32814

American (AMR) AF: 0.00 AC: 0 AN: 41760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25678

East Asian (EAS) AF: 0.00 AC: 0 AN: 38246

South Asian (SAS) AF: 0.00 AC: 0 AN: 82736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098514

Other (OTH) AF: 0.00 AC: 0 AN: 59360

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

Sep 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SH3BP2 protein function. 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. -

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
LIST_S2	Uncertain	0.91	.;D;.;.;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		4.7
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
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs121909146; hg19: chr4-2833309;