21-31124502-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001353694.2(TIAM1):c.4306+20G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,610,848 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0061 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (78 hom.)
• Consequence: TIAM1 NM_001353694.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.765

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 21-31124502-C-T is Benign according to our data. Variant chr21-31124502-C-T is described in ClinVar as [Benign]. Clinvar id is 2652582.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00749 (10922/1458578) while in subpopulation MID AF= 0.0275 (122/4444). AF 95% confidence interval is 0.0235. There are 78 homozygotes in gnomad4_exome. There are 5654 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIAM1	NM_001353694.2	c.4306+20G>A		intron_variant		ENST00000541036.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIAM1	ENST00000541036.6	c.4306+20G>A		intron_variant		5	NM_001353694.2	P1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 925 AN: 152152 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00952

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00803

Gnomad OTH AF: 0.0139

GnomAD3 exomes AF: 0.00772 AC: 1929 AN: 249776 Hom.: 15 AF XY: 0.00859 AC XY: 1159 AN XY: 134976

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00770

Gnomad ASJ exome AF: 0.0237

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.0116

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00864

Gnomad OTH exome AF: 0.0115

GnomAD4 exome AF: 0.00749 AC: 10922 AN: 1458578 Hom.: 78 Cov.: 30 AF XY: 0.00779 AC XY: 5654 AN XY: 725572

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.00846

Gnomad4 ASJ exome AF: 0.0240

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0114

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.00736

Gnomad4 OTH exome AF: 0.00944

GnomAD4 genome AF: 0.00606 AC: 923 AN: 152270 Hom.: 4 Cov.: 32 AF XY: 0.00600 AC XY: 447 AN XY: 74458

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.0103

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00803

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00866 Hom.: 3

Bravo AF: 0.00694

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2023

TIAM1: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	1.4
Dann	Benign	0.85

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: rs148777323; hg19: chr21-32496820;