NM_001353694.2:c.4306+20G>A

Variant names:

• chr21-31124502-C-T
• rs148777323
• NM_001353694.2:c.4306+20G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.765
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with language delay and seizures

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 2652582.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 5654 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353694.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIAM1	NM_001353694.2	MANE Select	c.4306+20G>A		intron	N/A	NP_001340623.1	Q13009-1
	TIAM1	NM_001353688.1		c.4306+20G>A		intron	N/A	NP_001340617.1	Q13009-1
	TIAM1	NM_001353689.1		c.4306+20G>A		intron	N/A	NP_001340618.1	Q13009-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIAM1	ENST00000541036.6	TSL:5 MANE Select	c.4306+20G>A		intron	N/A	ENSP00000441570.2	Q13009-1
	TIAM1	ENST00000698169.1		c.4326G>A	p.Thr1442Thr	synonymous	Exon 27 of 28	ENSP00000513591.1	A0A8V8TN84
	TIAM1	ENST00000923710.1		c.4384+20G>A		intron	N/A	ENSP00000593769.1

Frequencies

GnomAD3 genomes AF: 0.00608 AC: 925 AN: 152152 Hom.: 4 Cov.: 32

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

GnomAD2 exomes AF: 0.00772 AC: 1929 AN: 249776 AF XY: 0.00859

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 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.: 78 Cov.: 30 AF XY: 0.00779 AC XY: 5654 AN XY: 725572

African (AFR) AF: 0.00141 AC: 47 AN: 33382

American (AMR) AF: 0.00846 AC: 377 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.0240 AC: 626 AN: 26054

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39618

South Asian (SAS) AF: 0.0114 AC: 975 AN: 85824

European-Finnish (FIN) AF: 0.000431 AC: 23 AN: 53378

Middle Eastern (MID) AF: 0.0275 AC: 122 AN: 4444

European-Non Finnish (NFE) AF: 0.00736 AC: 8182 AN: 1111174

Other (OTH) AF: 0.00944 AC: 568 AN: 60162

GnomAD4 genome AF: 0.00606 AC: 923 AN: 152270 Hom.: 4 Cov.: 32 AF XY: 0.00600 AC XY: 447 AN XY: 74458

African (AFR) AF: 0.00120 AC: 50 AN: 41554

American (AMR) AF: 0.0103 AC: 157 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00803 AC: 546 AN: 68018

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.00866 Hom.: 3

Bravo AF: 0.00694

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	1.4
DANN	Benign	0.85
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs148777323; hg19: chr21-32496820;