21-31355338-T-C

Position:

• chr21-31355338-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000653041.1(ENSG00000286643):​n.292-1973T>C variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 151,880 control chromosomes in the GnomAD database, including 8,082 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (8082 hom., cov: 31)
• Consequence: ENST00000653041.1 intron, non_coding_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00

Genes affected

(HGNC:):

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIAM1	NM_001353688.1	c.-653-15916A>G		intron_variant			NP_001340617.1
TIAM1	NM_001353689.1	c.-368-15916A>G		intron_variant			NP_001340618.1
TIAM1	NM_001353690.1	c.-368-15916A>G		intron_variant			NP_001340619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
	ENST00000653041.1	n.292-1973T>C		intron_variant, non_coding_transcript_variant
TIAM1	ENST00000286827.7	c.-368-15916A>G		intron_variant		5		ENSP00000286827	P1
TIAM1	ENST00000469412.5	n.113-15916A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47671 AN: 151760 Hom.: 8068 Cov.: 31

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.300

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.312

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.314 AC: 47713 AN: 151880 Hom.: 8082 Cov.: 31 AF XY: 0.317 AC XY: 23539 AN XY: 74206

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.428

Gnomad4 ASJ AF: 0.300

Gnomad4 EAS AF: 0.403

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.391

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.314

Alfa AF: 0.345 Hom.: 15607

Bravo AF: 0.319

Asia WGS AF: 0.301 AC: 1044 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.19
DANN	Benign	0.35

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: rs16988159; hg19: chr21-32727653;