21-31120718-C-CG
Variant names:
Variant summary
Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2
The NM_001353694.2(TIAM1):c.4425dupC(p.Gly1476ArgfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TIAM1
NM_001353694.2 frameshift
NM_001353694.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.61
Publications
0 publications found
Genes affected
TIAM1 (HGNC:11805): (TIAM Rac1 associated GEF 1) This gene encodes a RAC1-specific guanine nucleotide exchange factor (GEF). GEFs mediate the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP). The binding of GTP induces a conformational change in RAC1 that allows downstream effectors to bind and transduce a signal. This gene thus regulates RAC1 signaling pathways that affect cell shape, migration, adhesion, growth, survival, and polarity, as well as influencing actin cytoskeletal formation, endocytosis, and membrane trafficking. This gene thus plays an important role in cell invasion, metastasis, and carcinogenesis. In addition to RAC1, the encoded protein activates additional Rho-like GTPases such as CDC42, RAC2, RAC3 and RHOA. This gene encodes multiple protein isoforms that experience a diverse array of intramolecular, protein-protein, and phosphorylation interactions as well as phosphoinositide binding. Both the longer and shorter isoforms have C-terminal Dbl homology (DH) and pleckstrin homology (PH) domains while only the longer isoforms of this gene have the N-terminal myristoylation site and the downstream N-terminal PH domain, ras-binding domain (RBD), and PSD-95/DlgA/ZO-1 (PDZ) domain. [provided by RefSeq, Jul 2017]
TIAM1 Gene-Disease associations (from GenCC):
- neurodevelopmental disorder with language delay and seizuresInheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001353694.2. 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 |
|---|---|---|---|---|---|---|---|---|---|
| TIAM1 | NM_001353694.2 | MANE Select | c.4425dupC | p.Gly1476ArgfsTer6 | frameshift | Exon 28 of 28 | NP_001340623.1 | Q13009-1 | |
| TIAM1 | NM_001353688.1 | c.4425dupC | p.Gly1476ArgfsTer6 | frameshift | Exon 30 of 30 | NP_001340617.1 | Q13009-1 | ||
| TIAM1 | NM_001353689.1 | c.4425dupC | p.Gly1476ArgfsTer6 | frameshift | Exon 29 of 29 | NP_001340618.1 | Q13009-1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TIAM1 | ENST00000541036.6 | TSL:5 MANE Select | c.4425dupC | p.Gly1476ArgfsTer6 | frameshift | Exon 28 of 28 | ENSP00000441570.2 | Q13009-1 | |
| TIAM1 | ENST00000923710.1 | c.4503dupC | p.Gly1502ArgfsTer6 | frameshift | Exon 30 of 30 | ENSP00000593769.1 | |||
| TIAM1 | ENST00000286827.7 | TSL:5 | c.4425dupC | p.Gly1476ArgfsTer6 | frameshift | Exon 29 of 29 | ENSP00000286827.3 | Q13009-1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00 AC: 0AN: 251230 AF XY: 0.00
GnomAD2 exomes
AF:
AC:
0
AN:
251230
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461824Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 727208 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
1
AN:
1461824
Hom.:
Cov.:
36
AF XY:
AC XY:
0
AN XY:
727208
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33478
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
AC:
1
AN:
53370
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111998
Other (OTH)
AF:
AC:
0
AN:
60394
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
-
1
-
TIAM1-related disorder (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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