22-37644882-C-G

Variant names:

• chr22-37644882-C-G
• rs960519170
• NM_018957.6:c.700C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018957.6(SH3BP1):​c.700C>G​(p.Gln234Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000212 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SH3BP1 NM_018957.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

Genes affected

SH3BP1 (HGNC:10824): (SH3 domain binding protein 1) This gene encodes a member of the Rho GTPase activating protein (RhoGAP) family. The encoded protein regulates Rac signaling and plays a role in cytoskeletal dynamics, cell motility and epithelial junction formation. This protein's association with the exocyst complex, which tethers secretory vesicles to the plasma membrane, has been demonstrated to be important in cell motility. In a distinct complex, this protein has been shown to regulate epithelial junction formation and morphogenesis. By interacting with the Plexin-D1 cell surface receptor, this protein mediates changes in the cytoskeleton in response to semaphorin binding. This protein may promote metastasis in human liver cancer cells and tissues. [provided by RefSeq, Mar 2017]

ENSG00000285304 (HGNC:):

PDXP-DT (HGNC:40525): (PDXP divergent transcript)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH3BP1	NM_018957.6	c.700C>G	p.Gln234Glu	missense_variant	Exon 9 of 18	ENST00000649765.2	NP_061830.3
SH3BP1	NM_001350055.2	c.700C>G	p.Gln234Glu	missense_variant	Exon 9 of 18		NP_001336984.1
PDXP-DT	NR_109952.1	n.678-1121G>C		intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH3BP1	ENST00000649765.2	c.700C>G	p.Gln234Glu	missense_variant	Exon 9 of 18		NM_018957.6	ENSP00000497104.1
ENSG00000285304	ENST00000451997.6	c.508C>G	p.Gln170Glu	missense_variant	Exon 8 of 17	2		ENSP00000401076.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461722 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.700C>G (p.Q234E) alteration is located in exon 9 (coding exon 9) of the SH3BP1 gene. This alteration results from a C to G substitution at nucleotide position 700, causing the glutamine (Q) at amino acid position 234 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.9	M;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0040	D;.;.
Polyphen		0.98	D;D;.
Vest4		0.86
MutPred		0.70		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;
MVP		0.80
MPC		0.60
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs960519170; hg19: chr22-38040889;