rs73199525

Variant names:

• chr21-31512535-G-A
• rs73199525
• NM_001353688.1:c.-707+46392C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-31512535-G-A
• chr21-31512535-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003253.3(TIAM1):​c.-422+46392C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0244 in 151,760 control chromosomes in the GnomAD database, including 54 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 0.024 (54 hom., cov: 32)
• Consequence: TIAM1 NM_003253.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0244 (3702/151760) while in subpopulation NFE AF= 0.0362 (2459/67952). AF 95% confidence interval is 0.035. There are 54 homozygotes in gnomad4. There are 1802 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIAM1	NM_001353688.1	c.-707+46392C>T		intron_variant	Intron 1 of 29		NP_001340617.1
TIAM1	NM_001353689.1	c.-489+46392C>T		intron_variant	Intron 1 of 28		NP_001340618.1
TIAM1	NM_001353690.1	c.-369+46392C>T		intron_variant	Intron 1 of 27		NP_001340619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIAM1	ENST00000286827.7	c.-422+46392C>T		intron_variant	Intron 1 of 28	5		ENSP00000286827.3
TIAM1	ENST00000469412.5	n.59+47384C>T		intron_variant	Intron 1 of 8	2

Frequencies

GnomAD3 genomes AF: 0.0244 AC: 3698 AN: 151670 Hom.: 54 Cov.: 32

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.0357

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0362

Gnomad OTH AF: 0.0177

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

GnomAD4 genome AF: 0.0244 AC: 3702 AN: 151760 Hom.: 54 Cov.: 32 AF XY: 0.0243 AC XY: 1802 AN XY: 74112

Gnomad4 AFR AF: 0.00628

Gnomad4 AMR AF: 0.0292

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0138

Gnomad4 FIN AF: 0.0357

Gnomad4 NFE AF: 0.0362

Gnomad4 OTH AF: 0.0176

Alfa AF: 0.0267 Hom.: 11

Bravo AF: 0.0231

Asia WGS AF: 0.00664 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.78

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: rs73199525; hg19: chr21-32884848;