21-31355338-T-C

Variant names:

• chr21-31355338-T-C
• rs16988159
• NM_001353688.1:c.-653-15916A>G

Variant summary

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

The NM_001353688.1(TIAM1):​c.-653-15916A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 151,880 control chromosomes in the GnomAD database, including 8,082 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 0.31 (8082 hom., cov: 31)
• Consequence: TIAM1 NM_001353688.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00
• Publications: 2 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

ENSG00000286643 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.42 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.-653-15916A>G		intron	N/A	NP_001340617.1
	TIAM1	NM_001353689.1		c.-368-15916A>G		intron	N/A	NP_001340618.1
	TIAM1	NM_001353690.1		c.-368-15916A>G		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.-368-15916A>G		intron	N/A	ENSP00000286827.3
	TIAM1	ENST00000469412.5	TSL:2	n.113-15916A>G		intron	N/A
	ENSG00000286643	ENST00000653041.1		n.292-1973T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47671 AN: 151760 Hom.: 8068 Cov.: 31

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.312

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

GnomAD4 genome AF: 0.314 AC: 47713 AN: 151880 Hom.: 8082 Cov.: 31 AF XY: 0.317 AC XY: 23539 AN XY: 74206

African (AFR) AF: 0.188 AC: 7805 AN: 41452

American (AMR) AF: 0.428 AC: 6541 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 1041 AN: 3472

East Asian (EAS) AF: 0.403 AC: 2070 AN: 5134

South Asian (SAS) AF: 0.242 AC: 1166 AN: 4810

European-Finnish (FIN) AF: 0.391 AC: 4106 AN: 10500

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24029 AN: 67928

Other (OTH) AF: 0.314 AC: 662 AN: 2110

Alfa AF: 0.341 Hom.: 34722

Bravo AF: 0.319

Asia WGS AF: 0.301 AC: 1044 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.19
DANN	Benign	0.35
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: rs16988159; hg19: chr21-32727653;