NM_001122681.2:c.-4-2080G>A

Variant names:

• chr4-2818534-G-A
• rs28562583
• NM_001122681.2:c.-4-2080G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001122681.2(SH3BP2):​c.-4-2080G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0896 in 521,254 control chromosomes in the GnomAD database, including 2,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (865 hom., cov: 33)
  • Exomes 𝑓: 0.085 (1579 hom.)
• Consequence: SH3BP2 NM_001122681.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.510
• Publications: 3 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 4-2818534-G-A is Benign according to our data. Variant chr4-2818534-G-A is described in ClinVar as [Benign]. Clinvar id is 1264442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.-4-2080G>A		intron_variant	Intron 1 of 12	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.167+144G>A		intron_variant	Intron 1 of 12		NP_001139328.1
SH3BP2	NM_001145855.2	c.81-2080G>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.-4-2080G>A		intron_variant	Intron 1 of 12	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15466 AN: 152114 Hom.: 865 Cov.: 33

Gnomad AFR AF: 0.0917

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0710

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.0904

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.124

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.105

GnomAD4 exome AF: 0.0847 AC: 31248 AN: 369032 Hom.: 1579 AF XY: 0.0851 AC XY: 15160 AN XY: 178056

African (AFR) AF: 0.0775 AC: 538 AN: 6942

American (AMR) AF: 0.0517 AC: 129 AN: 2494

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 346 AN: 4334

East Asian (EAS) AF: 0.00436 AC: 45 AN: 10328

South Asian (SAS) AF: 0.0815 AC: 519 AN: 6368

European-Finnish (FIN) AF: 0.160 AC: 1454 AN: 9108

Middle Eastern (MID) AF: 0.116 AC: 115 AN: 990

European-Non Finnish (NFE) AF: 0.0860 AC: 27004 AN: 314180

Other (OTH) AF: 0.0768 AC: 1098 AN: 14288

GnomAD4 genome AF: 0.102 AC: 15466 AN: 152222 Hom.: 865 Cov.: 33 AF XY: 0.104 AC XY: 7719 AN XY: 74416

African (AFR) AF: 0.0915 AC: 3803 AN: 41546

American (AMR) AF: 0.0710 AC: 1086 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0861 AC: 299 AN: 3472

East Asian (EAS) AF: 0.0110 AC: 57 AN: 5178

South Asian (SAS) AF: 0.0902 AC: 436 AN: 4832

European-Finnish (FIN) AF: 0.182 AC: 1925 AN: 10604

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.110 AC: 7505 AN: 67970

Other (OTH) AF: 0.105 AC: 221 AN: 2110

Alfa AF: 0.0660 Hom.: 88

Bravo AF: 0.0918

Asia WGS AF: 0.0540 AC: 189 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 16, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	17
DANN	Uncertain	0.98
PhyloP100		0.51
PromoterAI		-0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs28562583; hg19: chr4-2820261;