ENST00000356331.10:n.163C>T

Variant names:

• chr4-2818976-C-T
• rs78035476
• ENST00000356331.10:n.163C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000356331.10(SH3BP2):​n.163C>T variant causes a non coding transcript exon 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 ENST00000356331.10 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0450
• 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 -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

African (AFR) AF: 0.00679 AC: 93 AN: 13702

American (AMR) AF: 0.0739 AC: 64 AN: 866

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 64 AN: 4484

East Asian (EAS) AF: 0.0336 AC: 106 AN: 3152

South Asian (SAS) AF: 0.0235 AC: 336 AN: 14302

European-Finnish (FIN) AF: 0.00826 AC: 2 AN: 242

Middle Eastern (MID) AF: 0.0184 AC: 26 AN: 1416

European-Non Finnish (NFE) AF: 0.0280 AC: 18590 AN: 664812

Other (OTH) AF: 0.0244 AC: 585 AN: 23948

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

African (AFR) AF: 0.0110 AC: 459 AN: 41554

American (AMR) AF: 0.0497 AC: 760 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3472

East Asian (EAS) AF: 0.0391 AC: 203 AN: 5194

South Asian (SAS) AF: 0.0237 AC: 114 AN: 4808

European-Finnish (FIN) AF: 0.0138 AC: 146 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0260 AC: 1772 AN: 68026

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

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
PhyloP100		-0.045
PromoterAI		-0.00030	Neutral
Mutation Taster		=299/1	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: rs78035476; hg19: chr4-2820703;