21-31124646-C-T

Position:

• chr21-31124646-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001353694.2(TIAM1):​c.4182G>A​(p.Leu1394=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00084 in 1,612,408 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (7 hom.)
• Consequence: TIAM1 NM_001353694.2 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.478

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 21-31124646-C-T is Benign according to our data. Variant chr21-31124646-C-T is described in ClinVar as [Benign]. Clinvar id is 3034467.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000781 (1140/1460108) while in subpopulation AMR AF= 0.016 (714/44502). AF 95% confidence interval is 0.0151. There are 7 homozygotes in gnomad4_exome. There are 487 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIAM1	NM_001353694.2	c.4182G>A	p.Leu1394=	synonymous_variant	27/28	ENST00000541036.6	NP_001340623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIAM1	ENST00000541036.6	c.4182G>A	p.Leu1394=	synonymous_variant	27/28	5	NM_001353694.2	ENSP00000441570	P1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00926

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00324 AC: 808 AN: 249488 Hom.: 4 AF XY: 0.00253 AC XY: 341 AN XY: 134832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0106

Gnomad SAS exome AF: 0.000363

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.000781 AC: 1140 AN: 1460108 Hom.: 7 Cov.: 30 AF XY: 0.000671 AC XY: 487 AN XY: 726312

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0160

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00802

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.000895

GnomAD4 genome AF: 0.00141 AC: 214 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74478

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00908

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000458 Hom.: 1

Bravo AF: 0.00277

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000595

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TIAM1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2024

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
BayesDel_noAF	Benign	-0.30
CADD	Benign	2.9
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs192535474; hg19: chr21-32496964;