4-2818976-C-T

Variant names:

• chr4-2818976-C-T
• rs78035476
• NM_001122681.2:c.-4-1638C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003023.4(SH3BP2):​c.-99C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 879,210 control chromosomes in the GnomAD database, including 367 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (85 hom., cov: 33)
  • Exomes 𝑓: 0.027 (282 hom.)
• Consequence: SH3BP2 NM_003023.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0450

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-2818976-C-T is Benign according to our data. Variant chr4-2818976-C-T is described in ClinVar as [Benign]. Clinvar id is 348561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.-4-1638C>T		intron_variant	Intron 1 of 12	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_003023.4	c.-99C>T		5_prime_UTR_variant	Exon 1 of 13		NP_003014.3
SH3BP2	NM_001145856.2	c.167+586C>T		intron_variant	Intron 1 of 12		NP_001139328.1
SH3BP2	NM_001145855.2	c.81-1638C>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.-4-1638C>T		intron_variant	Intron 1 of 12	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3553 AN: 152168 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0491

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.0390

Gnomad SAS AF: 0.0237

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.0273 AC: 19866 AN: 726924 Hom.: 282 Cov.: 9 AF XY: 0.0272 AC XY: 9214 AN XY: 338130

Gnomad4 AFR exome AF: 0.00679

Gnomad4 AMR exome AF: 0.0739

Gnomad4 ASJ exome AF: 0.0143

Gnomad4 EAS exome AF: 0.0336

Gnomad4 SAS exome AF: 0.0235

Gnomad4 FIN exome AF: 0.00826

Gnomad4 NFE exome AF: 0.0280

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0234 AC: 3560 AN: 152286 Hom.: 85 Cov.: 33 AF XY: 0.0225 AC XY: 1674 AN XY: 74452

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0497

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.0391

Gnomad4 SAS AF: 0.0237

Gnomad4 FIN AF: 0.0138

Gnomad4 NFE AF: 0.0260

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0224 Hom.: 7

Bravo AF: 0.0260

Asia WGS AF: 0.0440 AC: 153 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.5
DANN	Benign	0.75

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: rs78035476; hg19: chr4-2820703;