chr21-31124502-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001353694.2(TIAM1):​c.4306+20G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,588 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TIAM1 NM_001353694.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.765
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).

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>T		intron	N/A	NP_001340623.1	Q13009-1
	TIAM1	NM_001353688.1		c.4306+20G>T		intron	N/A	NP_001340617.1	Q13009-1
	TIAM1	NM_001353689.1		c.4306+20G>T		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>T		intron	N/A	ENSP00000441570.2	Q13009-1
	TIAM1	ENST00000698169.1		c.4326G>T	p.Thr1442Thr	synonymous	Exon 27 of 28	ENSP00000513591.1	A0A8V8TN84
	TIAM1	ENST00000923710.1		c.4384+20G>T		intron	N/A	ENSP00000593769.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458588 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725578

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 85828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4446

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111178

Other (OTH) AF: 0.00 AC: 0 AN: 60162

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.51
DANN	Benign	0.81
PhyloP100		-0.77

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;