21-31445194-A-G

Variant names:

• chr21-31445194-A-G
• rs580140
• NM_001353688.1:c.-654+18789T>C

Variant summary

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

The NM_001353688.1(TIAM1):​c.-654+18789T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 151,946 control chromosomes in the GnomAD database, including 6,744 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 0.29 (6744 hom., cov: 31)
• Consequence: TIAM1 NM_001353688.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.493
• Publications: 10 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353688.1. 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_001353688.1		c.-654+18789T>C		intron	N/A	NP_001340617.1
	TIAM1	NM_001353689.1		c.-369+18722T>C		intron	N/A	NP_001340618.1
	TIAM1	NM_001353690.1		c.-368-105772T>C		intron	N/A	NP_001340619.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIAM1	ENST00000286827.7	TSL:5	c.-369+18789T>C		intron	N/A	ENSP00000286827.3
	TIAM1	ENST00000469412.5	TSL:2	n.112+18789T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44204 AN: 151830 Hom.: 6727 Cov.: 31

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.282

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

GnomAD4 genome AF: 0.291 AC: 44253 AN: 151946 Hom.: 6744 Cov.: 31 AF XY: 0.288 AC XY: 21407 AN XY: 74290

African (AFR) AF: 0.377 AC: 15596 AN: 41400

American (AMR) AF: 0.233 AC: 3547 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 934 AN: 3470

East Asian (EAS) AF: 0.120 AC: 621 AN: 5164

South Asian (SAS) AF: 0.330 AC: 1585 AN: 4808

European-Finnish (FIN) AF: 0.234 AC: 2472 AN: 10564

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18629 AN: 67978

Other (OTH) AF: 0.280 AC: 589 AN: 2106

Alfa AF: 0.273 Hom.: 18009

Bravo AF: 0.293

Asia WGS AF: 0.232 AC: 810 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.1
DANN	Benign	0.61
PhyloP100		0.49
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: rs580140; hg19: chr21-32817507;