4-2818236-G-C

Variant names:

• chr4-2818236-G-C
• rs1314437432
• ENST00000511747.6:c.13G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_001122681.2(SH3BP2):​c.-4-2378G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000607 in 988,086 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: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: SH3BP2 NM_001122681.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.353
• Publications: 0 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35485724).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000271 (4/147560) while in subpopulation AMR AF = 0.000202 (3/14882). AF 95% confidence interval is 0.0000542. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.-4-2378G>C		intron_variant	Intron 1 of 12	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.13G>C	p.Gly5Arg	missense_variant	Exon 1 of 13		NP_001139328.1
SH3BP2	NM_001145855.2	c.81-2378G>C		intron_variant	Intron 1 of 12		NP_001139327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.-4-2378G>C		intron_variant	Intron 1 of 12	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.0000271 AC: 4 AN: 147560 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000490

GnomAD4 exome AF: 0.00000238 AC: 2 AN: 840526 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 388924

African (AFR) AF: 0.00 AC: 0 AN: 15916

American (AMR) AF: 0.00 AC: 0 AN: 1268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5302

East Asian (EAS) AF: 0.00 AC: 0 AN: 3898

South Asian (SAS) AF: 0.00 AC: 0 AN: 17232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1640

European-Non Finnish (NFE) AF: 0.00000261 AC: 2 AN: 766536

Other (OTH) AF: 0.00 AC: 0 AN: 27728

GnomAD4 genome AF: 0.0000271 AC: 4 AN: 147560 Hom.: 0 Cov.: 32 AF XY: 0.0000417 AC XY: 3 AN XY: 71860

African (AFR) AF: 0.00 AC: 0 AN: 40864

American (AMR) AF: 0.000202 AC: 3 AN: 14882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3404

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66378

Other (OTH) AF: 0.000490 AC: 1 AN: 2042

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13G>C (p.G5R) alteration is located in exon 1 (coding exon 1) of the SH3BP2 gene. This alteration results from a G to C substitution at nucleotide position 13, causing the glycine (G) at amino acid position 5 to be replaced by an arginine (R). 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	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.36	T
PhyloP100		0.35
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.29	N
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Vest4		0.35
MutPred		0.30		Gain of methylation at G5 (P = 0.0186);
MVP		0.60
MPC		0.19
ClinPred		0.21	T
GERP RS		1.5
PromoterAI		-0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=96/4	polymorphism

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: rs1314437432; hg19: chr4-2819963;