rs148117486

Positions:

• chr4-2820651-A-C
• chr4-2820651-A-G
• chr4-2820651-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001122681.2(SH3BP2):​c.34A>C​(p.Met12Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M12V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SH3BP2 NM_001122681.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.60

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.34A>C	p.Met12Leu	missense_variant	2/13	ENST00000503393.8
SH3BP2	NM_001145856.2	c.205A>C	p.Met69Leu	missense_variant	2/13
SH3BP2	NM_001145855.2	c.118A>C	p.Met40Leu	missense_variant	2/13
SH3BP2	NM_003023.4	c.34A>C	p.Met12Leu	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.34A>C	p.Met12Leu	missense_variant	2/13	1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251440 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461844 Hom.: 0 Cov.: 39 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.27	T;.;.;T;T;.;.;.;T;T;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	.;.;D;D;D;D;D;D;.;.;D;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.;.;.;L;L;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.29
Sift	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.73	P;.;.;.;.;.;.;.;P;P;.;P
Vest4		0.58
MutPred		0.49		Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);.;Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);Gain of methylation at K13 (P = 0.0408);.;Gain of methylation at K13 (P = 0.0408);
MVP		0.86
MPC		0.65
ClinPred		0.69	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64

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

LitVar

Other links and lift over

dbSNP: rs148117486; hg19: chr4-2822378;