rs190648042

Variant names:

• chr4-2833834-A-G
• rs190648042
• NM_001122681.2:c.1686A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_001122681.2(SH3BP2):​c.1686A>G​(p.Ter562Trpext*?) 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:4
• Conservation: PhyloP100: 6.39
• Publications: 5 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), Orphanet, G2P, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 106 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001122681.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	NM_001122681.2	MANE Select	c.1686A>G	p.Ter562Trpext*?	stop_lost	Exon 13 of 13	NP_001116153.1	A0A384N6E5
	SH3BP2	NM_001145856.2		c.1857A>G	p.Ter619Trpext*?	stop_lost	Exon 13 of 13	NP_001139328.1	P78314-4
	SH3BP2	NM_001145855.2		c.1770A>G	p.Ter590Trpext*?	stop_lost	Exon 13 of 13	NP_001139327.1	P78314-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH3BP2	ENST00000503393.8	TSL:1 MANE Select	c.1686A>G	p.Ter562Trpext*?	stop_lost	Exon 13 of 13	ENSP00000422168.3	P78314-1
	SH3BP2	ENST00000511747.6	TSL:1	c.1857A>G	p.Ter619Trpext*?	stop_lost	Exon 13 of 13	ENSP00000424846.2	P78314-4
	SH3BP2	ENST00000356331.10	TSL:1	n.1947A>G		non_coding_transcript_exon	Exon 13 of 13

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

GnomAD2 exomes AF: 0.000583 AC: 102 AN: 175060 AF XY: 0.000585

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 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

African (AFR) AF: 0.000155 AC: 5 AN: 32360

American (AMR) AF: 0.0000781 AC: 3 AN: 38388

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25380

East Asian (EAS) AF: 0.00 AC: 0 AN: 37056

South Asian (SAS) AF: 0.00 AC: 0 AN: 81270

European-Finnish (FIN) AF: 0.00317 AC: 146 AN: 46060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5244

European-Non Finnish (NFE) AF: 0.000899 AC: 978 AN: 1087384

Other (OTH) AF: 0.000530 AC: 31 AN: 58498

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

African (AFR) AF: 0.000193 AC: 8 AN: 41554

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68020

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000893 Hom.: 1

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fibrous dysplasia of jaw (3)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		6.4
Vest4		0.24
GERP RS		5.6
Mutation Taster		=200/0	disease causing (ClinVar)

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: rs190648042; hg19: chr4-2835561;