rs845930

Positions:

• chr21-31347809-A-C
• chr21-31347809-A-G

Variant summary

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

The ENST00000653041.1(ENSG00000286643):​n.74A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 149,240 control chromosomes in the GnomAD database, including 32,959 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 0.67 (32959 hom., cov: 32)
• Consequence: ENST00000653041.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.488

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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIAM1	NM_001353688.1	c.-653-8387T>G		intron_variant			NP_001340617.1
TIAM1	NM_001353689.1	c.-368-8387T>G		intron_variant			NP_001340618.1
TIAM1	NM_001353690.1	c.-368-8387T>G		intron_variant			NP_001340619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
	ENST00000653041.1	n.74A>C		non_coding_transcript_exon_variant	1/3
TIAM1	ENST00000286827.7	c.-368-8387T>G		intron_variant		5		ENSP00000286827	P1
TIAM1	ENST00000469412.5	n.113-8387T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.668 AC: 99599 AN: 149120 Hom.: 32928 Cov.: 32

Gnomad AFR AF: 0.763

Gnomad AMI AF: 0.743

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.741

Gnomad EAS AF: 0.553

Gnomad SAS AF: 0.740

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.806

Gnomad NFE AF: 0.642

Gnomad OTH AF: 0.679

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

GnomAD4 genome AF: 0.668 AC: 99677 AN: 149240 Hom.: 32959 Cov.: 32 AF XY: 0.665 AC XY: 48540 AN XY: 72980

Gnomad4 AFR AF: 0.763

Gnomad4 AMR AF: 0.576

Gnomad4 ASJ AF: 0.741

Gnomad4 EAS AF: 0.553

Gnomad4 SAS AF: 0.739

Gnomad4 FIN AF: 0.604

Gnomad4 NFE AF: 0.642

Gnomad4 OTH AF: 0.678

Alfa AF: 0.673 Hom.: 7173

Bravo AF: 0.694

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.4
DANN	Benign	0.14

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: rs845930; hg19: chr21-32720124;