4-2839513-T-C

Variant names:

• chr4-2839513-T-C
• rs4690002
• ENST00000356331.10:n.7626T>C

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.7626T>C 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 0.668 in 151,978 control chromosomes in the GnomAD database, including 34,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34164 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH3BP2 ENST00000356331.10 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.75
• Publications: 9 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

ENSG00000296107 (HGNC:58714):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BP6: Variant 4-2839513-T-C is Benign according to our data. Variant chr4-2839513-T-C is described in ClinVar as Benign. ClinVar VariationId is 348689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000356331.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	NM_001122681.2	MANE Select	c.*5679T>C		3_prime_UTR	Exon 13 of 13	NP_001116153.1
	SH3BP2	NM_001145856.2		c.*5679T>C		3_prime_UTR	Exon 13 of 13	NP_001139328.1
	SH3BP2	NM_001145855.2		c.*5679T>C		3_prime_UTR	Exon 13 of 13	NP_001139327.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000356331.10	TSL:1	n.7626T>C		non_coding_transcript_exon	Exon 13 of 13
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.*5679T>C		3_prime_UTR	Exon 13 of 13	ENSP00000422168.3
	SH3BP2	ENST00000513020.6	TSL:3	n.*7246T>C		non_coding_transcript_exon	Exon 14 of 14	ENSP00000424072.1

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101382 AN: 151862 Hom.: 34111 Cov.: 31

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.700

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.665

Gnomad FIN AF: 0.660

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.665

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.668 AC: 101491 AN: 151978 Hom.: 34164 Cov.: 31 AF XY: 0.668 AC XY: 49643 AN XY: 74274

African (AFR) AF: 0.745 AC: 30870 AN: 41440

American (AMR) AF: 0.700 AC: 10682 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2382 AN: 3472

East Asian (EAS) AF: 0.502 AC: 2592 AN: 5168

South Asian (SAS) AF: 0.666 AC: 3207 AN: 4816

European-Finnish (FIN) AF: 0.660 AC: 6955 AN: 10536

Middle Eastern (MID) AF: 0.753 AC: 220 AN: 292

European-Non Finnish (NFE) AF: 0.625 AC: 42472 AN: 67964

Other (OTH) AF: 0.669 AC: 1413 AN: 2112

Alfa AF: 0.635 Hom.: 8974

Bravo AF: 0.674

Asia WGS AF: 0.643 AC: 2236 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 12, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.57
DANN	Benign	0.58
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4690002; hg19: chr4-2841240;