rs2409411

Variant names:

• chr21-31548091-C-T
• rs2409411
• NM_001353688.1:c.-707+10836G>A

Variant summary

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

The NM_001353688.1(TIAM1):​c.-707+10836G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 148,770 control chromosomes in the GnomAD database, including 15,856 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 0.45 (15856 hom., cov: 30)
• Consequence: TIAM1 NM_001353688.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0440
• Publications: 6 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIAM1	NM_001353688.1	c.-707+10836G>A		intron_variant	Intron 1 of 29		NP_001340617.1
TIAM1	NM_001353689.1	c.-489+10836G>A		intron_variant	Intron 1 of 28		NP_001340618.1
TIAM1	NM_001353690.1	c.-369+10836G>A		intron_variant	Intron 1 of 27		NP_001340619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIAM1	ENST00000286827.7	c.-422+10836G>A		intron_variant	Intron 1 of 28	5		ENSP00000286827.3
TIAM1	ENST00000469412.5	n.59+11828G>A		intron_variant	Intron 1 of 8	2

Frequencies

GnomAD3 genomes AF: 0.446 AC: 66277 AN: 148680 Hom.: 15823 Cov.: 30

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.375

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.490

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.449

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

GnomAD4 genome AF: 0.446 AC: 66363 AN: 148770 Hom.: 15856 Cov.: 30 AF XY: 0.446 AC XY: 32245 AN XY: 72292

African (AFR) AF: 0.629 AC: 25515 AN: 40578

American (AMR) AF: 0.455 AC: 6784 AN: 14906

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1551 AN: 3450

East Asian (EAS) AF: 0.225 AC: 1110 AN: 4936

South Asian (SAS) AF: 0.375 AC: 1766 AN: 4710

European-Finnish (FIN) AF: 0.386 AC: 3665 AN: 9494

Middle Eastern (MID) AF: 0.497 AC: 144 AN: 290

European-Non Finnish (NFE) AF: 0.365 AC: 24600 AN: 67440

Other (OTH) AF: 0.448 AC: 926 AN: 2066

Alfa AF: 0.426 Hom.: 1883

Bravo AF: 0.457

Asia WGS AF: 0.318 AC: 1107 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.65
DANN	Benign	0.48
PhyloP100		0.044
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: rs2409411; hg19: chr21-32920404;