rs2833362

Variant names:

• chr21-31283082-C-T
• rs2833362
• NM_001353694.2:c.-188-6174G>A

Variant summary

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

The NM_001353694.2(TIAM1):​c.-188-6174G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 152,262 control chromosomes in the GnomAD database, including 178 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 0.028 (178 hom., cov: 32)
• Consequence: TIAM1 NM_001353694.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780
• 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 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=-0.75).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0896 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIAM1	NM_001353694.2	MANE Select	c.-188-6174G>A		intron	N/A	NP_001340623.1
	TIAM1	NM_001353688.1		c.-473-6174G>A		intron	N/A	NP_001340617.1
	TIAM1	NM_001353689.1		c.-188-6174G>A		intron	N/A	NP_001340618.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIAM1	ENST00000541036.6	TSL:5 MANE Select	c.-188-6174G>A		intron	N/A	ENSP00000441570.2
	TIAM1	ENST00000286827.7	TSL:5	c.-188-6174G>A		intron	N/A	ENSP00000286827.3
	TIAM1	ENST00000698169.1		c.-188-6174G>A		intron	N/A	ENSP00000513591.1

Frequencies

GnomAD3 genomes AF: 0.0276 AC: 4196 AN: 152144 Hom.: 177 Cov.: 32

Gnomad AFR AF: 0.0922

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00969

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.0244

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

GnomAD4 genome AF: 0.0276 AC: 4198 AN: 152262 Hom.: 178 Cov.: 32 AF XY: 0.0261 AC XY: 1943 AN XY: 74454

African (AFR) AF: 0.0920 AC: 3821 AN: 41532

American (AMR) AF: 0.00962 AC: 147 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.00366 AC: 19 AN: 5186

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4822

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00153 AC: 104 AN: 68032

Other (OTH) AF: 0.0241 AC: 51 AN: 2116

Alfa AF: 0.0121 Hom.: 27

Bravo AF: 0.0322

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.7
DANN	Benign	0.85
PhyloP100		-0.078
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: rs2833362; hg19: chr21-32655397;