chr21-31127155-A-G

Position:

• chr21-31127155-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001353694.2(TIAM1):​c.4046-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 1,612,182 control chromosomes in the GnomAD database, including 214,365 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.57 (25839 hom., cov: 34)
  • Exomes 𝑓: 0.50 (188526 hom.)
• Consequence: TIAM1 NM_001353694.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003661
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.126

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 21-31127155-A-G is Benign according to our data. Variant chr21-31127155-A-G is described in ClinVar as [Benign]. Clinvar id is 3059392.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIAM1	NM_001353694.2	c.4046-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000541036.6	NP_001340623.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIAM1	ENST00000541036.6	c.4046-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001353694.2	ENSP00000441570	P1

Frequencies

GnomAD3 genomes AF: 0.573 AC: 87176 AN: 152046 Hom.: 25814 Cov.: 34

Gnomad AFR AF: 0.724

Gnomad AMI AF: 0.551

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.596

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.547

GnomAD3 exomes AF: 0.543 AC: 136470 AN: 251314 Hom.: 38175 AF XY: 0.528 AC XY: 71735 AN XY: 135824

Gnomad AFR exome AF: 0.735

Gnomad AMR exome AF: 0.666

Gnomad ASJ exome AF: 0.531

Gnomad EAS exome AF: 0.612

Gnomad SAS exome AF: 0.434

Gnomad FIN exome AF: 0.550

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.522

GnomAD4 exome AF: 0.504 AC: 735815 AN: 1460016 Hom.: 188526 Cov.: 33 AF XY: 0.500 AC XY: 363138 AN XY: 726326

Gnomad4 AFR exome AF: 0.744

Gnomad4 AMR exome AF: 0.660

Gnomad4 ASJ exome AF: 0.530

Gnomad4 EAS exome AF: 0.596

Gnomad4 SAS exome AF: 0.437

Gnomad4 FIN exome AF: 0.552

Gnomad4 NFE exome AF: 0.489

Gnomad4 OTH exome AF: 0.510

GnomAD4 genome AF: 0.573 AC: 87258 AN: 152166 Hom.: 25839 Cov.: 34 AF XY: 0.576 AC XY: 42882 AN XY: 74408

Gnomad4 AFR AF: 0.724

Gnomad4 AMR AF: 0.617

Gnomad4 ASJ AF: 0.530

Gnomad4 EAS AF: 0.594

Gnomad4 SAS AF: 0.450

Gnomad4 FIN AF: 0.547

Gnomad4 NFE AF: 0.487

Gnomad4 OTH AF: 0.545

Alfa AF: 0.508 Hom.: 40570

Bravo AF: 0.590

Asia WGS AF: 0.514 AC: 1789 AN: 3478

EpiCase AF: 0.486

EpiControl AF: 0.487

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

Oct 17, 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
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.2
DANN	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000037
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.050		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: rs2070410; hg19: chr21-32499473; COSMIC: COSV54580911;