rs13048019

Variant names:

• chr21-31545981-C-T
• rs13048019
• NM_001353688.1:c.-707+12946G>A

Variant summary

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

The NM_001353688.1(TIAM1):​c.-707+12946G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 151,962 control chromosomes in the GnomAD database, including 1,690 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 0.14 (1690 hom., cov: 32)
• Consequence: TIAM1 NM_001353688.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.181
• Publications: 19 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIAM1	NM_001353688.1	c.-707+12946G>A		intron_variant	Intron 1 of 29		NP_001340617.1
TIAM1	NM_001353689.1	c.-489+12946G>A		intron_variant	Intron 1 of 28		NP_001340618.1
TIAM1	NM_001353690.1	c.-369+12946G>A		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.-422+12946G>A		intron_variant	Intron 1 of 28	5		ENSP00000286827.3
TIAM1	ENST00000469412.5	n.59+13938G>A		intron_variant	Intron 1 of 8	2

Frequencies

GnomAD3 genomes AF: 0.138 AC: 21017 AN: 151844 Hom.: 1690 Cov.: 32

Gnomad AFR AF: 0.0719

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.0949

Gnomad FIN AF: 0.172

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.138

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

GnomAD4 genome AF: 0.138 AC: 21025 AN: 151962 Hom.: 1690 Cov.: 32 AF XY: 0.138 AC XY: 10254 AN XY: 74274

African (AFR) AF: 0.0718 AC: 2976 AN: 41468

American (AMR) AF: 0.165 AC: 2518 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 645 AN: 3468

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5176

South Asian (SAS) AF: 0.0947 AC: 456 AN: 4814

European-Finnish (FIN) AF: 0.172 AC: 1806 AN: 10524

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.179 AC: 12179 AN: 67946

Other (OTH) AF: 0.138 AC: 291 AN: 2110

Alfa AF: 0.160 Hom.: 4543

Bravo AF: 0.134

Asia WGS AF: 0.0750 AC: 262 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.1
DANN	Benign	0.45
PhyloP100		-0.18
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: rs13048019; hg19: chr21-32918294;