4-2818270-C-T

Variant names:

• chr4-2818270-C-T
• rs868817457
• ENST00000511747.6:c.47C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001145856.2(SH3BP2):​c.47C>T​(p.Ala16Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,013,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000092 (0 hom.)
• Consequence: SH3BP2 NM_001145856.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.192
• 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), Orphanet, G2P, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1240581).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000816 (12/146984) while in subpopulation AFR AF = 0.00022 (9/40976). AF 95% confidence interval is 0.000114. There are 0 homozygotes in GnomAd4. There are 5 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 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145856.2. 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.-4-2344C>T		intron	N/A	NP_001116153.1	A0A384N6E5
	SH3BP2	NM_001145856.2		c.47C>T	p.Ala16Val	missense	Exon 1 of 13	NP_001139328.1	P78314-4
	SH3BP2	NM_001145855.2		c.81-2344C>T		intron	N/A	NP_001139327.1	P78314-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000511747.6	TSL:1	c.47C>T	p.Ala16Val	missense	Exon 1 of 13	ENSP00000424846.2	P78314-4
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.-4-2344C>T		intron	N/A	ENSP00000422168.3	P78314-1
	SH3BP2	ENST00000932792.1		c.-125C>T		5_prime_UTR	Exon 1 of 12	ENSP00000602851.1

Frequencies

GnomAD3 genomes AF: 0.0000817 AC: 12 AN: 146882 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000303

Gnomad OTH AF: 0.000495

GnomAD4 exome AF: 0.00000923 AC: 8 AN: 866930 Hom.: 0 Cov.: 28 AF XY: 0.00000744 AC XY: 3 AN XY: 403244

African (AFR) AF: 0.000303 AC: 5 AN: 16514

American (AMR) AF: 0.00 AC: 0 AN: 2042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6060

East Asian (EAS) AF: 0.00 AC: 0 AN: 5470

South Asian (SAS) AF: 0.00 AC: 0 AN: 17564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1794

European-Non Finnish (NFE) AF: 0.00000383 AC: 3 AN: 784232

Other (OTH) AF: 0.00 AC: 0 AN: 29390

GnomAD4 genome AF: 0.0000816 AC: 12 AN: 146984 Hom.: 0 Cov.: 32 AF XY: 0.0000699 AC XY: 5 AN XY: 71552

African (AFR) AF: 0.000220 AC: 9 AN: 40976

American (AMR) AF: 0.00 AC: 0 AN: 14834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3386

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8706

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

European-Non Finnish (NFE) AF: 0.0000303 AC: 2 AN: 65946

Other (OTH) AF: 0.000490 AC: 1 AN: 2040

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	SH3BP2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	8.8
DANN	Uncertain	0.98
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.34	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.90	T
PhyloP100		-0.19
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.16
Sift	Benign	0.19	T
Vest4		0.10
MutPred		0.22		Loss of helix (P = 0.0304)
MVP		0.42
MPC		0.16
ClinPred		0.10	T
GERP RS		0.55
PromoterAI		-0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs868817457; hg19: chr4-2819997;