21-31120738-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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 (★).

• Frequency:
  • Genomes: 𝑓 0.0087 (9 hom., cov: 32)
  • Exomes 𝑓: 0.013 (148 hom.)
• Consequence: TIAM1 NM_001353694.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.646

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 Benign. Variant got -10 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 criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIAM1	NM_001353694.2	c.4406A>G	p.Lys1469Arg	missense_variant	28/28	ENST00000541036.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIAM1	ENST00000541036.6	c.4406A>G	p.Lys1469Arg	missense_variant	28/28	5	NM_001353694.2	P1

Frequencies

GnomAD3 genomes AF: 0.00874 AC: 1329 AN: 152126 Hom.: 9 Cov.: 32

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.: 17 AF XY: 0.00822 AC XY: 1116 AN XY: 135812

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.: 36 AF XY: 0.0124 AC XY: 9023 AN XY: 727224

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.: 9 Cov.: 32 AF XY: 0.00771 AC XY: 574 AN XY: 74430

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.: 24

Bravo AF: 0.00791

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0143 AC: 123

ExAC AF: 0.00841 AC: 1021

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.0113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TIAM1-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	18
Dann	Uncertain	0.98
DEOGEN2	Benign	0.053	T;.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.77	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;.;.
MutationTaster	Benign	0.98	N;N
PrimateAI	Benign	0.36	T
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	T
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

Other links and lift over

dbSNP: rs111536576; hg19: chr21-32493056; COSMIC: COSV99067187; COSMIC: COSV99067187;