4-2818312-C-T

Variant names:

• chr4-2818312-C-T
• rs1343869508
• ENST00000511747.6:c.89C>T

Variant summary

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

The NM_001122681.2(SH3BP2):​c.-4-2302C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,105,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SH3BP2 NM_001122681.2 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.66
• 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), G2P, Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.11494297).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000189 (28/147956) while in subpopulation AMR AF = 0.000402 (6/14940). AF 95% confidence interval is 0.000174. There are 0 homozygotes in GnomAd4. There are 13 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 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.-4-2302C>T		intron_variant	Intron 1 of 12	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145856.2	c.89C>T	p.Pro30Leu	missense_variant	Exon 1 of 13		NP_001139328.1
SH3BP2	NM_001145855.2	c.81-2302C>T		intron_variant	Intron 1 of 12		NP_001139327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.-4-2302C>T		intron_variant	Intron 1 of 12	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.000189 AC: 28 AN: 147856 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000402

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: 0.000226

Gnomad OTH AF: 0.000985

GnomAD4 exome AF: 0.000180 AC: 172 AN: 957126 Hom.: 0 Cov.: 30 AF XY: 0.000183 AC XY: 82 AN XY: 448892

African (AFR) AF: 0.000160 AC: 3 AN: 18786

American (AMR) AF: 0.000889 AC: 4 AN: 4500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9366

East Asian (EAS) AF: 0.00 AC: 0 AN: 15406

South Asian (SAS) AF: 0.00 AC: 0 AN: 18334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2258

European-Non Finnish (NFE) AF: 0.000185 AC: 156 AN: 841106

Other (OTH) AF: 0.000257 AC: 9 AN: 34998

GnomAD4 genome AF: 0.000189 AC: 28 AN: 147956 Hom.: 0 Cov.: 32 AF XY: 0.000180 AC XY: 13 AN XY: 72116

African (AFR) AF: 0.000122 AC: 5 AN: 41022

American (AMR) AF: 0.000402 AC: 6 AN: 14940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9092

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

European-Non Finnish (NFE) AF: 0.000226 AC: 15 AN: 66348

Other (OTH) AF: 0.000975 AC: 2 AN: 2052

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.000325

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.89C>T (p.P30L) alteration is located in exon 1 (coding exon 1) of the SH3BP2 gene. This alteration results from a C to T substitution at nucleotide position 89, causing the proline (P) at amino acid position 30 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Uncertain	0.98
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.32	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.87	T
PhyloP100		-1.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.21
Sift	Benign	0.032	D
Vest4		0.11
MutPred		0.21		Gain of MoRF binding (P = 0.0366);
MVP		0.31
MPC		0.17
ClinPred		0.24	T
GERP RS		1.7
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=92/8	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: rs1343869508; hg19: chr4-2820039;