rs190648042

Positions:

• chr4-2833834-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_001122681.2(SH3BP2):​c.1686A>G​(p.Ter562TrpextTer30) variant causes a stop lost change. The variant allele was found at a frequency of 0.000812 in 1,563,928 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (1 hom.)
• Consequence: SH3BP2 NM_001122681.2 stop_lost
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 6.39

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 -14 ACMG points.

• PM4: Stoplost variant in NM_001122681.2 Downstream stopcodon found after 580 codons.
• BP6: Variant 4-2833834-A-G is Benign according to our data. Variant chr4-2833834-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 525208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000696 (106/152288) while in subpopulation NFE AF= 0.00109 (74/68020). AF 95% confidence interval is 0.000888. There are 1 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 106 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH3BP2	NM_001122681.2	c.1686A>G	p.Ter562TrpextTer30	stop_lost	13/13	ENST00000503393.8
SH3BP2	NM_001145856.2	c.1857A>G	p.Ter619TrpextTer30	stop_lost	13/13
SH3BP2	NM_001145855.2	c.1770A>G	p.Ter590TrpextTer30	stop_lost	13/13
SH3BP2	NM_003023.4	c.1686A>G	p.Ter562TrpextTer30	stop_lost	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH3BP2	ENST00000503393.8	c.1686A>G	p.Ter562TrpextTer30	stop_lost	13/13	1	NM_001122681.2	P2

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152170 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000583 AC: 102 AN: 175060 Hom.: 0 AF XY: 0.000585 AC XY: 55 AN XY: 94078

Gnomad AFR exome AF: 0.000380

Gnomad AMR exome AF: 0.0000740

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00296

Gnomad NFE exome AF: 0.000704

Gnomad OTH exome AF: 0.000836

GnomAD4 exome AF: 0.000825 AC: 1164 AN: 1411640 Hom.: 1 Cov.: 31 AF XY: 0.000791 AC XY: 552 AN XY: 698222

Gnomad4 AFR exome AF: 0.000155

Gnomad4 AMR exome AF: 0.0000781

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00317

Gnomad4 NFE exome AF: 0.000899

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152288 Hom.: 1 Cov.: 33 AF XY: 0.000739 AC XY: 55 AN XY: 74464

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000904 Hom.: 0

Bravo AF: 0.000446

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000438 AC: 52

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibrous dysplasia of jaw Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.83
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	N;N;N;N;N;N
Vest4		0.24
GERP RS		5.6

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: rs190648042; hg19: chr4-2835561;