21-31120504-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM5 BP4_Strong

The NM_001353694.2(TIAM1):c.4640C>T(p.Ala1547Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000923 in 1,614,182 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1547E) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000094 (5 hom.)
• Consequence: TIAM1 NM_001353694.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.95

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 Likely_benign. Variant got -2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-31120504-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1693481.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.017931819).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIAM1	NM_001353694.2	c.4640C>T	p.Ala1547Val	missense_variant	28/28	ENST00000541036.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIAM1	ENST00000541036.6	c.4640C>T	p.Ala1547Val	missense_variant	28/28	5	NM_001353694.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000175 AC: 44 AN: 251378 Hom.: 1 AF XY: 0.000265 AC XY: 36 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000937 AC: 137 AN: 1461890 Hom.: 5 Cov.: 30 AF XY: 0.000150 AC XY: 109 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7 AN XY: 74456

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2022

The c.4640C>T (p.A1547V) alteration is located in exon 29 (coding exon 25) of the TIAM1 gene. This alteration results from a C to T substitution at nucleotide position 4640, causing the alanine (A) at amino acid position 1547 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.067	T;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.74	N;N;.
REVEL	Benign	0.058
Sift	Benign	0.10	T;T;.
Sift4G	Benign	0.14	T;T;.
Polyphen		0.0020	B;.;.
Vest4		0.20
MutPred		0.16		Gain of helix (P = 0.0164);.;.;
MVP		0.32
MPC		0.25
ClinPred		0.035	T
GERP RS		4.1
Varity_R		0.044
gMVP		0.24

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: rs760187500; hg19: chr21-32492822; COSMIC: COSV54546769; COSMIC: COSV54546769;