chr22-37639806-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018957.6(SH3BP1):​c.19C>T​(p.His7Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000446 in 1,568,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SH3BP1
NM_018957.6 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.22789314).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SH3BP1NM_018957.6 linkc.19C>T p.His7Tyr missense_variant Exon 1 of 18 ENST00000649765.2 NP_061830.3 Q9Y3L3-1A0A2X0SFX7
SH3BP1NM_001350055.2 linkc.19C>T p.His7Tyr missense_variant Exon 1 of 18 NP_001336984.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SH3BP1ENST00000649765.2 linkc.19C>T p.His7Tyr missense_variant Exon 1 of 18 NM_018957.6 ENSP00000497104.1 Q9Y3L3-1
ENSG00000285304ENST00000451997 linkc.-131C>T 5_prime_UTR_variant Exon 1 of 17 2 ENSP00000401076.2 F8WEQ3
SH3BP1ENST00000417536.5 linkn.19C>T non_coding_transcript_exon_variant Exon 2 of 20 2 ENSP00000411979.1 Q9Y3L3-2
SH3BP1ENST00000644149.1 linkn.112C>T non_coding_transcript_exon_variant Exon 1 of 17

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152148
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000141
AC:
2
AN:
1416434
Hom.:
0
Cov.:
31
AF XY:
0.00000285
AC XY:
2
AN XY:
701892
show subpopulations
Gnomad4 AFR exome
AF:
0.0000649
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152148
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74318
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.00000854
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 25, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.19C>T (p.H7Y) alteration is located in exon 1 (coding exon 1) of the SH3BP1 gene. This alteration results from a C to T substitution at nucleotide position 19, causing the histidine (H) at amino acid position 7 to be replaced by a tyrosine (Y). 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
0.17
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Uncertain
24
DANN
Benign
0.96
DEOGEN2
Benign
0.050
T;T
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.31
N
LIST_S2
Pathogenic
0.98
.;D
M_CAP
Uncertain
0.29
D
MetaRNN
Benign
0.23
T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
0.95
L;L
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
-1.6
N;.
REVEL
Benign
0.12
Sift
Benign
1.0
T;.
Sift4G
Benign
0.15
T;.
Polyphen
0.98
D;D
Vest4
0.35
MutPred
0.48
Gain of methylation at K3 (P = 0.1098);Gain of methylation at K3 (P = 0.1098);
MVP
0.59
MPC
1.8
ClinPred
0.21
T
GERP RS
2.8
Varity_R
0.16
gMVP
0.077

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

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

Other links and lift over

dbSNP: rs767021540; hg19: chr22-38035813; API