rs147432096

Variant names:

• chr4-2823037-G-A
• rs147432096
• NM_001122681.2:c.239G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-2823037-G-A
• chr4-2823037-G-C
• chr4-2823037-G-T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001122681.2(SH3BP2):​c.239G>A​(p.Arg80Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000617 in 1,610,560 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (3 hom.)
• Consequence: SH3BP2 NM_001122681.2 missense, splice_region
• Scores: Splicing: ADA: 0.9973
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.89
• Publications: 5 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), Orphanet, G2P, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 4-2823037-G-A is Benign according to our data. Variant chr4-2823037-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 348568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000565 (86/152172) while in subpopulation NFE AF = 0.00106 (72/68012). AF 95% confidence interval is 0.000861. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 86 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	NM_001122681.2	MANE Select	c.239G>A	p.Arg80Gln	missense splice_region	Exon 3 of 13	NP_001116153.1	A0A384N6E5
	SH3BP2	NM_001145856.2		c.410G>A	p.Arg137Gln	missense splice_region	Exon 3 of 13	NP_001139328.1	P78314-4
	SH3BP2	NM_001145855.2		c.323G>A	p.Arg108Gln	missense splice_region	Exon 3 of 13	NP_001139327.1	P78314-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.239G>A	p.Arg80Gln	missense splice_region	Exon 3 of 13	ENSP00000422168.3	P78314-1
	SH3BP2	ENST00000511747.6	TSL:1	c.410G>A	p.Arg137Gln	missense splice_region	Exon 3 of 13	ENSP00000424846.2	P78314-4
	SH3BP2	ENST00000356331.10	TSL:1	n.500G>A		splice_region non_coding_transcript_exon	Exon 3 of 13

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000357 AC: 89 AN: 249582 AF XY: 0.000348

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.000708

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000622 AC: 907 AN: 1458388 Hom.: 3 Cov.: 30 AF XY: 0.000613 AC XY: 445 AN XY: 725712

African (AFR) AF: 0.000150 AC: 5 AN: 33418

American (AMR) AF: 0.0000448 AC: 2 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86018

European-Finnish (FIN) AF: 0.0000939 AC: 5 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000770 AC: 854 AN: 1109260

Other (OTH) AF: 0.000614 AC: 37 AN: 60280

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.000511 AC XY: 38 AN XY: 74358

African (AFR) AF: 0.000217 AC: 9 AN: 41444

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68012

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000662 Hom.: 0

Bravo AF: 0.000506

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.000491

EpiControl AF: 0.000535

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fibrous dysplasia of jaw (2)
-	-	1	Intellectual disability (1)
-	-	1	SH3BP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.75
MVP		0.90
MPC		0.59
ClinPred		0.28	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.28
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
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: rs147432096; hg19: chr4-2824764;