4-2831573-G-C

Position:

• chr4-2831573-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001122681.2(SH3BP2):​c.1244G>C​(p.Arg415Pro) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R415Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH3BP2 NM_001122681.2 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 11 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 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-A is described in ClinVar as [Pathogenic]. Clinvar id is 7551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant 4-2831573-G-C is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.1244G>C	p.Arg415Pro	missense_variant, splice_region_variant	9/13	ENST00000503393.8
SH3BP2	NM_001145856.2	c.1415G>C	p.Arg472Pro	missense_variant, splice_region_variant	9/13
SH3BP2	NM_001145855.2	c.1328G>C	p.Arg443Pro	missense_variant, splice_region_variant	9/13
SH3BP2	NM_003023.4	c.1244G>C	p.Arg415Pro	missense_variant, splice_region_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1244G>C	p.Arg415Pro	missense_variant, splice_region_variant	9/13	1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Fibrous dysplasia of jaw Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;D;D;.;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;.;.;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0060	D;D;D;D;D;D
Sift4G	Benign	0.34	T;T;T;T;T;T
Polyphen		0.99	D;.;D;D;.;D
Vest4		0.71
MutPred		0.84		Gain of glycosylation at R415 (P = 0.0237);.;Gain of glycosylation at R415 (P = 0.0237);Gain of glycosylation at R415 (P = 0.0237);.;Gain of glycosylation at R415 (P = 0.0237);
MVP		0.97
MPC		0.79
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98

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;