rs2268225

Positions:

• chr21-31294488-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
TIAM1	NM_001353694.2	c.-188-17580A>G		intron_variant		ENST00000541036.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIAM1	ENST00000541036.6	c.-188-17580A>G		intron_variant		5	NM_001353694.2	P1
TIAM1	ENST00000286827.7	c.-188-17580A>G		intron_variant		5		P1
TIAM1	ENST00000698169.1	c.-188-17580A>G		intron_variant
TIAM1	ENST00000469412.5	n.293-42299A>G		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR AF: 0.230

Gnomad4 AMR AF: 0.180

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.381

Gnomad4 SAS AF: 0.223

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.204

Alfa AF: 0.223 Hom.: 5363

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

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

Other links and lift over

dbSNP: rs2268225; hg19: chr21-32666803;