rs2248656

Positions:

• chr21-31156642-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001353694.2(TIAM1):​c.2992-2216T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 152,238 control chromosomes in the GnomAD database, including 2,864 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 0.17 (2864 hom., cov: 32)
• Consequence: TIAM1 NM_001353694.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.912

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=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIAM1	NM_001353694.2	c.2992-2216T>C		intron_variant		ENST00000541036.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIAM1	ENST00000541036.6	c.2992-2216T>C		intron_variant		5	NM_001353694.2	P1

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26317 AN: 152120 Hom.: 2851 Cov.: 32

Gnomad AFR AF: 0.0678

Gnomad AMI AF: 0.0811

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.190

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

GnomAD4 genome AF: 0.173 AC: 26336 AN: 152238 Hom.: 2864 Cov.: 32 AF XY: 0.178 AC XY: 13237 AN XY: 74430

Gnomad4 AFR AF: 0.0677

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.270

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.189

Gnomad4 OTH AF: 0.194

Alfa AF: 0.184 Hom.: 3577

Bravo AF: 0.181

Asia WGS AF: 0.213 AC: 741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.6
DANN	Benign	0.88

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: rs2248656; hg19: chr21-32528960;