21-31439295-C-T

Variant names:

• chr21-31439295-C-T
• rs475142
• ENST00000923710.1:c.-369+24688G>A

Variant summary

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

The NM_003253.3(TIAM1):​c.-369+24688G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 152,114 control chromosomes in the GnomAD database, including 38,737 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 0.71 (38737 hom., cov: 33)
• Consequence: TIAM1 NM_003253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 3 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=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.801 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003253.3. 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_001353688.1		c.-654+24688G>A		intron	N/A	NP_001340617.1	Q13009-1
	TIAM1	NM_001353689.1		c.-369+24621G>A		intron	N/A	NP_001340618.1	Q13009-1
	TIAM1	NM_001353690.1		c.-368-99873G>A		intron	N/A	NP_001340619.1	Q13009-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIAM1	ENST00000923710.1		c.-369+24688G>A		intron	N/A	ENSP00000593769.1
	TIAM1	ENST00000286827.7	TSL:5	c.-369+24688G>A		intron	N/A	ENSP00000286827.3	Q13009-1
	TIAM1	ENST00000923707.1		c.-369+24621G>A		intron	N/A	ENSP00000593766.1

Frequencies

GnomAD3 genomes AF: 0.713 AC: 108312 AN: 151996 Hom.: 38715 Cov.: 33

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.689

Gnomad EAS AF: 0.773

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.624

Gnomad NFE AF: 0.696

Gnomad OTH AF: 0.704

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

GnomAD4 genome AF: 0.713 AC: 108385 AN: 152114 Hom.: 38737 Cov.: 33 AF XY: 0.714 AC XY: 53118 AN XY: 74360

African (AFR) AF: 0.718 AC: 29813 AN: 41496

American (AMR) AF: 0.726 AC: 11094 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.689 AC: 2387 AN: 3466

East Asian (EAS) AF: 0.773 AC: 3989 AN: 5160

South Asian (SAS) AF: 0.822 AC: 3963 AN: 4820

European-Finnish (FIN) AF: 0.706 AC: 7451 AN: 10558

Middle Eastern (MID) AF: 0.637 AC: 186 AN: 292

European-Non Finnish (NFE) AF: 0.696 AC: 47333 AN: 68010

Other (OTH) AF: 0.706 AC: 1492 AN: 2114

Alfa AF: 0.703 Hom.: 114602

Bravo AF: 0.708

Asia WGS AF: 0.794 AC: 2761 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.85
DANN	Benign	0.72
PhyloP100		-2.0
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: rs475142; hg19: chr21-32811608;