chr21-31479887-G-A

Variant names:

• chr21-31479887-G-A
• rs2833424
• NM_001353688.1:c.-706-15852C>T

Variant summary

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

The NM_001353688.1(TIAM1):​c.-706-15852C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.25 in 151,784 control chromosomes in the GnomAD database, including 5,271 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 0.25 (5271 hom., cov: 32)
• Consequence: TIAM1 NM_001353688.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 1 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIAM1	NM_001353688.1	c.-706-15852C>T		intron_variant	Intron 1 of 29		NP_001340617.1
TIAM1	NM_001353689.1	c.-488-15852C>T		intron_variant	Intron 1 of 28		NP_001340618.1
TIAM1	NM_001353690.1	c.-369+79040C>T		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.-421-15852C>T		intron_variant	Intron 1 of 28	5		ENSP00000286827.3
TIAM1	ENST00000469412.5	n.60-15852C>T		intron_variant	Intron 1 of 8	2

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37847 AN: 151666 Hom.: 5252 Cov.: 32

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.0821

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.249

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

GnomAD4 genome AF: 0.250 AC: 37902 AN: 151784 Hom.: 5271 Cov.: 32 AF XY: 0.247 AC XY: 18313 AN XY: 74176

African (AFR) AF: 0.377 AC: 15571 AN: 41354

American (AMR) AF: 0.195 AC: 2981 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 774 AN: 3468

East Asian (EAS) AF: 0.0821 AC: 421 AN: 5130

South Asian (SAS) AF: 0.254 AC: 1221 AN: 4808

European-Finnish (FIN) AF: 0.161 AC: 1694 AN: 10514

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14472 AN: 67940

Other (OTH) AF: 0.248 AC: 521 AN: 2104

Alfa AF: 0.222 Hom.: 1036

Bravo AF: 0.254

Asia WGS AF: 0.187 AC: 653 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.68
DANN	Benign	0.54
PhyloP100		-1.2
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: rs2833424; hg19: chr21-32852200;