rs2248656

Variant names:

• chr21-31156642-A-G
• rs2248656
• NM_001353694.2:c.2992-2216T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIAM1	NM_001353694.2	MANE Select	c.2992-2216T>C		intron	N/A	NP_001340623.1	Q13009-1
	TIAM1	NM_001353688.1		c.2992-2216T>C		intron	N/A	NP_001340617.1	Q13009-1
	TIAM1	NM_001353689.1		c.2992-2216T>C		intron	N/A	NP_001340618.1	Q13009-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIAM1	ENST00000541036.6	TSL:5 MANE Select	c.2992-2216T>C		intron	N/A	ENSP00000441570.2	Q13009-1
	TIAM1	ENST00000923710.1		c.2992-2216T>C		intron	N/A	ENSP00000593769.1
	TIAM1	ENST00000286827.7	TSL:5	c.2992-2216T>C		intron	N/A	ENSP00000286827.3	Q13009-1

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

African (AFR) AF: 0.0677 AC: 2816 AN: 41572

American (AMR) AF: 0.349 AC: 5335 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 584 AN: 3472

East Asian (EAS) AF: 0.270 AC: 1398 AN: 5170

South Asian (SAS) AF: 0.118 AC: 569 AN: 4820

European-Finnish (FIN) AF: 0.212 AC: 2251 AN: 10598

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12833 AN: 68004

Other (OTH) AF: 0.194 AC: 410 AN: 2114

Alfa AF: 0.181 Hom.: 5420

Bravo AF: 0.181

Asia WGS AF: 0.213 AC: 741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.6
DANN	Benign	0.88
PhyloP100		0.91
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: rs2248656; hg19: chr21-32528960;