rs2268225

Variant names:

• chr21-31294488-T-C
• rs2268225
• NM_001353694.2:c.-188-17580A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001353694.2(TIAM1):​c.-188-17580A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 152,096 control chromosomes in the GnomAD database, including 4,202 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4202 hom., cov: 32)
• Consequence: TIAM1 NM_001353694.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.379
• Publications: 5 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 seizures

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIAM1	NM_001353694.2	c.-188-17580A>G		intron_variant	Intron 2 of 27	ENST00000541036.6	NP_001340623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIAM1	ENST00000541036.6	c.-188-17580A>G		intron_variant	Intron 2 of 27	5	NM_001353694.2	ENSP00000441570.2
TIAM1	ENST00000286827.7	c.-188-17580A>G		intron_variant	Intron 3 of 28	5		ENSP00000286827.3
TIAM1	ENST00000698169.1	c.-188-17580A>G		intron_variant	Intron 2 of 27			ENSP00000513591.1
TIAM1	ENST00000469412.5	n.293-42299A>G		intron_variant	Intron 3 of 8	2

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35310 AN: 151978 Hom.: 4203 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.205

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.232 AC: 35330 AN: 152096 Hom.: 4202 Cov.: 32 AF XY: 0.234 AC XY: 17411 AN XY: 74346

African (AFR) AF: 0.230 AC: 9530 AN: 41504

American (AMR) AF: 0.180 AC: 2746 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 567 AN: 3470

East Asian (EAS) AF: 0.381 AC: 1969 AN: 5168

South Asian (SAS) AF: 0.223 AC: 1074 AN: 4816

European-Finnish (FIN) AF: 0.299 AC: 3157 AN: 10568

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15629 AN: 67982

Other (OTH) AF: 0.204 AC: 432 AN: 2116

Alfa AF: 0.229 Hom.: 13204

Bravo AF: 0.225

Asia WGS AF: 0.324 AC: 1123 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.37
PhyloP100		0.38
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: rs2268225; hg19: chr21-32666803;