21-31120738-T-C

Position:

chr21-31120738-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001353694.2(TIAM1):c.4406A>G(p.Lys1469Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,614,090 control chromosomes in the GnomAD database, including 157 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0087 ( 9 hom., cov: 32)

Exomes 𝑓: 0.013 ( 148 hom. )

Consequence

TIAM1
NM_001353694.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.646

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033746064).

BP6

Variant 21-31120738-T-C is Benign according to our data. Variant chr21-31120738-T-C is described in ClinVar as [Benign]. Clinvar id is 3042023.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIAM1	NM_001353694.2 linkuse as main transcript	c.4406A>G	p.Lys1469Arg	missense_variant	28/28	ENST00000541036.6	NP_001340623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIAM1	ENST00000541036.6 linkuse as main transcript	c.4406A>G	p.Lys1469Arg	missense_variant	28/28	5	NM_001353694.2	ENSP00000441570	P1	Q13009-1

Frequencies

GnomAD3 genomes

AF:

0.00874

AC:

1329

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00867

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0142

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00844

AC:

2119

AN:

251146

Hom.:

AF XY:

0.00822

AC XY:

1116

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00204

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.0128

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00310

Gnomad FIN exome

AF:

0.00855

Gnomad NFE exome

AF:

0.0133

Gnomad OTH exome

AF:

0.00882

GnomAD4 exome

AF:

0.0128

AC:

18736

AN:

1461846

Hom.:

148

Cov.:

AF XY:

0.0124

AC XY:

9023

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00333

Gnomad4 ASJ exome

AF:

0.0127

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00318

Gnomad4 FIN exome

AF:

0.00916

Gnomad4 NFE exome

AF:

0.0150

Gnomad4 OTH exome

AF:

0.0114

GnomAD4 genome

AF:

0.00873

AC:

1329

AN:

152244

Hom.:

Cov.:

AF XY:

0.00771

AC XY:

574

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00269

Gnomad4 AMR

AF:

0.00575

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.00867

Gnomad4 NFE

AF:

0.0142

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.0124

Hom.:

Bravo

AF:

0.00791

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0143

AC:

123

ExAC

AF:

0.00841

AC:

1021

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0111

EpiControl

AF:

0.0113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TIAM1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.053

T;.;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.77

T;T;T

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;.;.

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.040

N;N;.

REVEL

Benign

0.013

Sift

Benign

0.23

T;T;.

Sift4G

Benign

0.57

T;T;.

Polyphen

0.0010

B;.;.

Vest4

0.024

MVP

0.31

MPC

0.20

ClinPred

0.0080

GERP RS

-0.028

Varity_R

0.055

gMVP

0.11

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over