chr4-2827265-C-T

Variant names:

• chr4-2827265-C-T
• rs35313240
• NM_001122681.2:c.464C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001122681.2(SH3BP2):​c.464C>T​(p.Ala155Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00678 in 1,614,226 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. 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. A155T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0070 (54 hom.)
• Consequence: SH3BP2 NM_001122681.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.25
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006905973).
• BP6: Variant 4-2827265-C-T is Benign according to our data. Variant chr4-2827265-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 348574.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 = 0.00442 (674/152362) while in subpopulation NFE AF = 0.00753 (512/68038). AF 95% confidence interval is 0.00699. There are 4 homozygotes in GnomAd4. There are 296 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 674 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.464C>T	p.Ala155Val	missense	Exon 6 of 13	NP_001116153.1
	SH3BP2	NM_001145856.2		c.635C>T	p.Ala212Val	missense	Exon 6 of 13	NP_001139328.1
	SH3BP2	NM_001145855.2		c.548C>T	p.Ala183Val	missense	Exon 6 of 13	NP_001139327.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.464C>T	p.Ala155Val	missense	Exon 6 of 13	ENSP00000422168.3
	SH3BP2	ENST00000511747.6	TSL:1	c.635C>T	p.Ala212Val	missense	Exon 6 of 13	ENSP00000424846.2
	SH3BP2	ENST00000356331.10	TSL:1	n.725C>T		non_coding_transcript_exon	Exon 6 of 13

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 674 AN: 152244 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00752

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00532 AC: 1337 AN: 251428 AF XY: 0.00533

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00896

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00702 AC: 10267 AN: 1461864 Hom.: 54 Cov.: 32 AF XY: 0.00698 AC XY: 5078 AN XY: 727236

African (AFR) AF: 0.00143 AC: 48 AN: 33480

American (AMR) AF: 0.00302 AC: 135 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00509 AC: 133 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00246 AC: 212 AN: 86258

European-Finnish (FIN) AF: 0.00109 AC: 58 AN: 53414

Middle Eastern (MID) AF: 0.0142 AC: 82 AN: 5768

European-Non Finnish (NFE) AF: 0.00829 AC: 9215 AN: 1111992

Other (OTH) AF: 0.00636 AC: 384 AN: 60396

GnomAD4 genome AF: 0.00442 AC: 674 AN: 152362 Hom.: 4 Cov.: 33 AF XY: 0.00397 AC XY: 296 AN XY: 74506

African (AFR) AF: 0.00135 AC: 56 AN: 41580

American (AMR) AF: 0.00314 AC: 48 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4832

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00753 AC: 512 AN: 68038

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00720 Hom.: 13

Bravo AF: 0.00456

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00562 AC: 682

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00851

EpiControl AF: 0.00925

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Fibrous dysplasia of jaw (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.069
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0069	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.092
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.18	T
Polyphen		0.46	P
Vest4		0.21
MVP		0.90
MPC		0.18
ClinPred		0.011	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
Mutation Taster		=98/2	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: rs35313240; hg19: chr4-2828992; COSMIC: COSV100696908; COSMIC: COSV100696908;