21-31343131-C-T

Variant names:

• chr21-31343131-C-T
• rs2833383
• NM_001353694.2:c.-369+1007G>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.-369+1007G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 152,036 control chromosomes in the GnomAD database, including 3,894 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 0.22 (3894 hom., cov: 32)
• Consequence: TIAM1 NM_001353694.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 2 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIAM1	NM_001353694.2	c.-369+1007G>A		intron_variant	Intron 1 of 27	ENST00000541036.6	NP_001340623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIAM1	ENST00000541036.6	c.-369+1007G>A		intron_variant	Intron 1 of 27	5	NM_001353694.2	ENSP00000441570.2
TIAM1	ENST00000286827.7	c.-368-3709G>A		intron_variant	Intron 2 of 28	5		ENSP00000286827.3
TIAM1	ENST00000698169.1	c.-369+1007G>A		intron_variant	Intron 1 of 27			ENSP00000513591.1
TIAM1	ENST00000469412.5	n.113-3709G>A		intron_variant	Intron 2 of 8	2

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33132 AN: 151918 Hom.: 3895 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.234

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

GnomAD4 genome AF: 0.218 AC: 33139 AN: 152036 Hom.: 3894 Cov.: 32 AF XY: 0.214 AC XY: 15892 AN XY: 74324

African (AFR) AF: 0.245 AC: 10144 AN: 41428

American (AMR) AF: 0.168 AC: 2573 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1067 AN: 3472

East Asian (EAS) AF: 0.00445 AC: 23 AN: 5170

South Asian (SAS) AF: 0.291 AC: 1400 AN: 4818

European-Finnish (FIN) AF: 0.149 AC: 1575 AN: 10580

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15433 AN: 67982

Other (OTH) AF: 0.230 AC: 484 AN: 2108

Alfa AF: 0.228 Hom.: 13071

Bravo AF: 0.216

Asia WGS AF: 0.152 AC: 528 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.20
DANN	Benign	0.39
PhyloP100		-1.5
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: rs2833383; hg19: chr21-32715446;