NM_001122681.2:c.-4-8193A>G

Variant names:

• chr4-2812421-A-G
• rs1709004
• NM_001122681.2:c.-4-8193A>G

Variant summary

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

The NM_001122681.2(SH3BP2):​c.-4-8193A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0412 in 1,550,288 control chromosomes in the GnomAD database, including 3,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (1350 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1849 hom.)
• Consequence: SH3BP2 NM_001122681.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.10
• Publications: 2 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=-0.92).
• BP6: Variant 4-2812421-A-G is Benign according to our data. Variant chr4-2812421-A-G is described in ClinVar as [Benign]. Clinvar id is 1239506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP2	NM_001122681.2	c.-4-8193A>G		intron_variant	Intron 1 of 12	ENST00000503393.8	NP_001116153.1
SH3BP2	NM_001145855.2	c.24A>G	p.Thr8Thr	synonymous_variant	Exon 1 of 13		NP_001139327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP2	ENST00000503393.8	c.-4-8193A>G		intron_variant	Intron 1 of 12	1	NM_001122681.2	ENSP00000422168.3

Frequencies

GnomAD3 genomes AF: 0.0913 AC: 13888 AN: 152092 Hom.: 1343 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0781

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.0400

Gnomad SAS AF: 0.0245

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0695

GnomAD2 exomes AF: 0.0504 AC: 7552 AN: 149768 AF XY: 0.0449

Gnomad AFR exome AF: 0.247

Gnomad AMR exome AF: 0.0981

Gnomad ASJ exome AF: 0.0402

Gnomad EAS exome AF: 0.0396

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.0284

Gnomad OTH exome AF: 0.0455

GnomAD4 exome AF: 0.0358 AC: 50002 AN: 1398078 Hom.: 1849 Cov.: 31 AF XY: 0.0344 AC XY: 23713 AN XY: 689600

African (AFR) AF: 0.247 AC: 7799 AN: 31594

American (AMR) AF: 0.0945 AC: 3372 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 998 AN: 25156

East Asian (EAS) AF: 0.0618 AC: 2207 AN: 35732

South Asian (SAS) AF: 0.0247 AC: 1955 AN: 79226

European-Finnish (FIN) AF: 0.0141 AC: 681 AN: 48154

Middle Eastern (MID) AF: 0.0260 AC: 148 AN: 5694

European-Non Finnish (NFE) AF: 0.0281 AC: 30300 AN: 1078850

Other (OTH) AF: 0.0438 AC: 2542 AN: 57980

GnomAD4 genome AF: 0.0915 AC: 13925 AN: 152210 Hom.: 1350 Cov.: 33 AF XY: 0.0872 AC XY: 6490 AN XY: 74432

African (AFR) AF: 0.244 AC: 10118 AN: 41520

American (AMR) AF: 0.0785 AC: 1202 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3468

East Asian (EAS) AF: 0.0401 AC: 208 AN: 5186

South Asian (SAS) AF: 0.0243 AC: 117 AN: 4822

European-Finnish (FIN) AF: 0.0138 AC: 147 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0269 AC: 1828 AN: 67974

Other (OTH) AF: 0.0707 AC: 149 AN: 2108

Alfa AF: 0.0566 Hom.: 286

Bravo AF: 0.103

Asia WGS AF: 0.0700 AC: 244 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.83
DANN	Benign	0.74
PhyloP100		-1.1
PromoterAI		-0.019	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs1709004; hg19: chr4-2814148; COSMIC: COSV67748357; COSMIC: COSV67748357;