chr4-2818254-T-G

Position:

• chr4-2818254-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000503393.8(SH3BP2):​c.-4-2360T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000118 in 849,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: SH3BP2 ENST00000503393.8 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32032016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.-4-2360T>G		intron_variant		ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.31T>G	p.Trp11Gly	missense_variant	1/13		NP_001139328.1
SH3BP2	NM_001145855.2	c.81-2360T>G		intron_variant			NP_001139327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.-4-2360T>G		intron_variant		1	NM_001122681.2	ENSP00000422168	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000118 AC: 1 AN: 849702 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 394170

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: 0.00000129

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.31T>G (p.W11G) alteration is located in exon 1 (coding exon 1) of the SH3BP2 gene. This alteration results from a T to G substitution at nucleotide position 31, causing the tryptophan (W) at amino acid position 11 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.71
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.31	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	1.0	D;D;D;D;D;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Vest4		0.32
MutPred		0.27		Gain of relative solvent accessibility (P = 0.005);
MVP		0.70
MPC		0.29
ClinPred		0.27	T
GERP RS		1.7

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: rs1577352308; hg19: chr4-2819981;