Genetic Variant ENST00000511747.6:c.47C>A (chr4-2818270-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000511747.6(SH3BP2):c.47C>A(p.Ala16Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000115 in 866,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A16V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000012 ( 0 hom. )

Consequence

SH3BP2
ENST00000511747.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.192

Publications

0 publications found

Variant links:

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

SH3BP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13207555).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000511747.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3BP2	NM_001122681.2	MANE Select	c.-4-2344C>A		intron	N/A	NP_001116153.1	A0A384N6E5
SH3BP2	NM_001145856.2		c.47C>A	p.Ala16Glu	missense	Exon 1 of 13	NP_001139328.1	P78314-4
SH3BP2	NM_001145855.2		c.81-2344C>A		intron	N/A	NP_001139327.1	P78314-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH3BP2	ENST00000511747.6	TSL:1	c.47C>A	p.Ala16Glu	missense	Exon 1 of 13	ENSP00000424846.2	P78314-4
SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.-4-2344C>A		intron	N/A	ENSP00000422168.3	P78314-1
SH3BP2	ENST00000932792.1		c.-125C>A		5_prime_UTR	Exon 1 of 12	ENSP00000602851.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000115

AC:

AN:

866926

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

403240

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

16514

American (AMR)

AF:

0.00

AC:

AN:

2042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6060

East Asian (EAS)

AF:

0.00

AC:

AN:

5470

South Asian (SAS)

AF:

0.00

AC:

AN:

17562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1794

European-Non Finnish (NFE)

AF:

0.00000128

AC:

AN:

784230

Other (OTH)

AF:

0.00

AC:

AN:

29390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

7.0

(source)

DANN

Benign

0.93

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.29

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.90

PhyloP100

-0.19

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.19

REVEL

Benign

0.15

Sift

Benign

0.20

Vest4

0.12

MutPred

0.17

Gain of solvent accessibility (P = 0.0488)

MVP

0.42

MPC

0.19

ClinPred

0.11

GERP RS

0.55

PromoterAI

-0.0041

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over