21-31512535-G-A

Variant names:

• chr21-31512535-G-A
• rs73199525
• NM_001353688.1:c.-707+46392C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001353688.1(TIAM1):​c.-707+46392C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0244 in 151,760 control chromosomes in the GnomAD database, including 54 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 0.024 (54 hom., cov: 32)
• Consequence: TIAM1 NM_001353688.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100
• 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: 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=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0244 (3702/151760) while in subpopulation NFE AF = 0.0362 (2459/67952). AF 95% confidence interval is 0.035. There are 54 homozygotes in GnomAd4. There are 1802 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 54 AR gene

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.-707+46392C>T		intron	N/A	NP_001340617.1
	TIAM1	NM_001353689.1		c.-489+46392C>T		intron	N/A	NP_001340618.1
	TIAM1	NM_001353690.1		c.-369+46392C>T		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.-422+46392C>T		intron	N/A	ENSP00000286827.3
	TIAM1	ENST00000469412.5	TSL:2	n.59+47384C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3698 AN: 151670 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.0357

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0177

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

GnomAD4 genome AF: 0.0244 AC: 3702 AN: 151760 Hom.: 54 Cov.: 32 AF XY: 0.0243 AC XY: 1802 AN XY: 74112

African (AFR) AF: 0.00628 AC: 260 AN: 41386

American (AMR) AF: 0.0292 AC: 444 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.0138 AC: 66 AN: 4792

European-Finnish (FIN) AF: 0.0357 AC: 374 AN: 10478

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0362 AC: 2459 AN: 67952

Other (OTH) AF: 0.0176 AC: 37 AN: 2108

Alfa AF: 0.0331 Hom.: 145

Bravo AF: 0.0231

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.78
PhyloP100		0.0010
Mutation Taster		=100/0	polymorphism

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: rs73199525; hg19: chr21-32884848;