Genetic Variant NM_001353694.2:c.4306+20G>A (chr21-31124502-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.765

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 -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 GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIAM1	NM_001353694.2 link	c.4306+20G>A		intron_variant	Intron 27 of 27	ENST00000541036.6	NP_001340623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIAM1	ENST00000541036.6 link	c.4306+20G>A		intron_variant	Intron 27 of 27	5	NM_001353694.2	ENSP00000441570.2		Q13009-1

Frequencies

GnomAD3 genomes

AF:

0.00608

AC:

925

AN:

152152

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00859

AC XY:

1159

AN XY:

134976

show subpopulations

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.:

Cov.:

AF XY:

0.00779

AC XY:

5654

AN XY:

725572

show subpopulations

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.:

Cov.:

AF XY:

0.00600

AC XY:

447

AN XY:

74458

show subpopulations

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.:

Bravo

AF:

0.00694

Asia WGS

AF:

0.00433

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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