22-37641473-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_018957.6(SH3BP1):​c.202C>T​(p.Arg68Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,549,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SH3BP1
NM_018957.6 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.44
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SH3BP1NM_018957.6 linkc.202C>T p.Arg68Trp missense_variant Exon 3 of 18 ENST00000649765.2 NP_061830.3 Q9Y3L3-1A0A2X0SFX7
SH3BP1NM_001350055.2 linkc.202C>T p.Arg68Trp missense_variant Exon 3 of 18 NP_001336984.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SH3BP1ENST00000649765.2 linkc.202C>T p.Arg68Trp missense_variant Exon 3 of 18 NM_018957.6 ENSP00000497104.1 Q9Y3L3-1
ENSG00000285304ENST00000451997.6 linkc.10C>T p.Arg4Trp missense_variant Exon 2 of 17 2 ENSP00000401076.2 F8WEQ3

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000143
AC:
20
AN:
1397490
Hom.:
0
Cov.:
32
AF XY:
0.0000131
AC XY:
9
AN XY:
689266
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000280
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000167
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152202
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000283
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 21, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.202C>T (p.R68W) alteration is located in exon 3 (coding exon 3) of the SH3BP1 gene. This alteration results from a C to T substitution at nucleotide position 202, causing the arginine (R) at amino acid position 68 to be replaced by a tryptophan (W). 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
Pathogenic
0.89
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.41
T;T;.
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.98
.;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.84
D;D;D
MetaSVM
Benign
-0.65
T
MutationAssessor
Uncertain
2.9
M;M;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-7.2
D;.;D
REVEL
Uncertain
0.49
Sift
Pathogenic
0.0
D;.;.
Sift4G
Pathogenic
0.0
D;.;.
Polyphen
1.0
D;D;.
Vest4
0.81
MutPred
0.68
Loss of disorder (P = 0.0146);Loss of disorder (P = 0.0146);.;
MVP
0.52
MPC
1.5
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.84
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.26
Position offset: -2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1308020239; hg19: chr22-38037480; COSMIC: COSV100379299; COSMIC: COSV100379299; API