chr4-2831582-C-T

Position:

• chr4-2831582-C-T

Variant summary

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

The ENST00000503393.8(SH3BP2):​c.1253C>T​(p.Pro418Leu) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P418R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SH3BP2 ENST00000503393.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000503393.8
• 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-G is described in ClinVar as [Pathogenic]. Clinvar id is 7548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745
• PP5: Variant 4-2831582-C-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.1253C>T	p.Pro418Leu	missense_variant	9/13	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.1424C>T	p.Pro475Leu	missense_variant	9/13		NP_001139328.1
SH3BP2	NM_001145855.2	c.1337C>T	p.Pro446Leu	missense_variant	9/13		NP_001139327.1
SH3BP2	NM_003023.4	c.1253C>T	p.Pro418Leu	missense_variant	9/13		NP_003014.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1253C>T	p.Pro418Leu	missense_variant	9/13	1	NM_001122681.2	ENSP00000422168	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435998 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 711922

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: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jan 28, 2022	PS4, PM1, PM5, PM2, PP3, PP5 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -
Pathogenic, no assertion criteria provided	research	Clinical Genetics Laboratory, Federal University of Health Sciences of Porto Alegre	Mar 18, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 16, 2021	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, 18596838, 28644570, 23298620, 11381256). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect SH3BP2 protein function (PMID: 22153077). This variant has been observed in individuals and families affected with cherubism (PMID: 11381256, 27272835, 23298620). ClinVar contains an entry for this variant (Variation ID: 7547). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 418 of the SH3BP2 protein (p.Pro418Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.;D;D;.;D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;.;.;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.74	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.018	D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D
Polyphen		1.0	D;.;D;D;.;D
Vest4		0.44
MutPred		0.74		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		0.98
MPC		0.69
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.60

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;