21-31120439-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001353694.2(TIAM1):c.4705G>A(p.Ala1569Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000769 in 1,614,200 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (2 hom.)
• Consequence: TIAM1 NM_001353694.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.14

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033111572).
• BP6: Variant 21-31120439-C-T is Benign according to our data. Variant chr21-31120439-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3034617.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIAM1	NM_001353694.2	c.4705G>A	p.Ala1569Thr	missense_variant	28/28	ENST00000541036.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIAM1	ENST00000541036.6	c.4705G>A	p.Ala1569Thr	missense_variant	28/28	5	NM_001353694.2	P1

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000968 AC: 243 AN: 251150 Hom.: 1 AF XY: 0.000870 AC XY: 118 AN XY: 135694

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00419

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.000855

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000770 AC: 1125 AN: 1461870 Hom.: 2 Cov.: 30 AF XY: 0.000703 AC XY: 511 AN XY: 727238

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00212

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00180

Gnomad4 NFE exome AF: 0.000724

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.000762 AC: 116 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74482

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00100 Hom.: 3

Bravo AF: 0.000699

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000881 AC: 107

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000711

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TIAM1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 18, 2022

This variant is classified as likely 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	0.061
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.82
Dann	Benign	0.71
DEOGEN2	Benign	0.050	T;.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.61	T;T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.0033	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.33	N;N;.
REVEL	Benign	0.053
Sift	Benign	0.48	T;T;.
Sift4G	Benign	0.63	T;T;.
Polyphen		0.0010	B;.;.
Vest4		0.028
MVP		0.20
MPC		0.24
ClinPred		0.0032	T
GERP RS		-9.9
Varity_R		0.025
gMVP		0.10

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

Other links and lift over

dbSNP: rs146645440; hg19: chr21-32492757;