4-2818299-G-A

Variant names:

• chr4-2818299-G-A
• rs866128602
• ENST00000511747.6:c.76G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001122681.2(SH3BP2):​c.-4-2315G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,069,268 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: SH3BP2 NM_001122681.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00600
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061558843).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00171 (252/147416) while in subpopulation AFR AF = 0.00571 (234/40978). AF 95% confidence interval is 0.00511. There are 1 homozygotes in GnomAd4. There are 114 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
• BS2: High AC in GnomAd4 at 252 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.-4-2315G>A		intron_variant	Intron 1 of 12	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.76G>A	p.Gly26Arg	missense_variant	Exon 1 of 13		NP_001139328.1
SH3BP2	NM_001145855.2	c.81-2315G>A		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.-4-2315G>A		intron_variant	Intron 1 of 12	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 247 AN: 147314 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000876

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: 0.0000151

Gnomad OTH AF: 0.00197

GnomAD4 exome AF: 0.000142 AC: 131 AN: 921852 Hom.: 0 Cov.: 29 AF XY: 0.000151 AC XY: 65 AN XY: 431342

African (AFR) AF: 0.00639 AC: 114 AN: 17834

American (AMR) AF: 0.00 AC: 0 AN: 3522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8010

East Asian (EAS) AF: 0.00 AC: 0 AN: 11462

South Asian (SAS) AF: 0.0000555 AC: 1 AN: 18028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2090

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 818840

Other (OTH) AF: 0.000487 AC: 16 AN: 32826

GnomAD4 genome AF: 0.00171 AC: 252 AN: 147416 Hom.: 1 Cov.: 32 AF XY: 0.00159 AC XY: 114 AN XY: 71794

African (AFR) AF: 0.00571 AC: 234 AN: 40978

American (AMR) AF: 0.000874 AC: 13 AN: 14868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66124

Other (OTH) AF: 0.00195 AC: 4 AN: 2056

Alfa AF: 0.00169 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.76G>A (p.G26R) alteration is located in exon 1 (coding exon 1) of the SH3BP2 gene. This alteration results from a G to A substitution at nucleotide position 76, causing the glycine (G) at amino acid position 26 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	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Uncertain	0.98
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.82	T
PhyloP100		-0.0060
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Vest4		0.12
MutPred		0.18		Gain of methylation at G26 (P = 0.0095);
MVP		0.74
MPC		0.19
ClinPred		0.48	T
GERP RS		1.5
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=100/0	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: rs866128602; hg19: chr4-2820026;