5-134115951-C-T

Variant names:

• chr5-134115951-C-T
• rs1755765265
• NM_003202.5:c.359C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003202.5(TCF7):​c.359C>T​(p.Thr120Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

Genes affected

TCF7 (HGNC:11639): (transcription factor 7) This gene encodes a member of the T-cell factor/lymphoid enhancer-binding factor family of high mobility group (HMG) box transcriptional activators. This gene is expressed predominantly in T-cells and plays a critical role in natural killer cell and innate lymphoid cell development. The encoded protein forms a complex with beta-catenin and activates transcription through a Wnt/beta-catenin signaling pathway. Mice with a knockout of this gene are viable and fertile, but display a block in T-lymphocyte differentiation. Alternative splicing results in multiple transcript variants. Naturally-occurring isoforms lacking the N-terminal beta-catenin interaction domain may act as dominant negative regulators of Wnt signaling. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7	NM_003202.5	c.359C>T	p.Thr120Ile	missense_variant	Exon 3 of 10	ENST00000342854.10	NP_003193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF7	ENST00000342854.10	c.359C>T	p.Thr120Ile	missense_variant	Exon 3 of 10	1	NM_003202.5	ENSP00000340347.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461672 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727118

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.359C>T (p.T120I) alteration is located in exon 3 (coding exon 3) of the TCF7 gene. This alteration results from a C to T substitution at nucleotide position 359, causing the threonine (T) at amino acid position 120 to be replaced by an isoleucine (I). 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
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T;T;.;.;T;.;.;.;.
Eigen	Benign	0.014
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.2	N;D;D;N;N;N;N;N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.087	T;T;D;D;D;D;D;D;D;D
Sift4G	Benign	0.18	T;T;D;D;T;D;D;D;D;D
Polyphen		0.90	P;P;.;.;.;.;.;.;.;.
Vest4		0.59
MutPred		0.54		Loss of disorder (P = 0.0309);Loss of disorder (P = 0.0309);.;.;.;.;.;.;.;.;
MVP		0.95
MPC		0.59
ClinPred		0.89	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.63

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: rs1755765265; hg19: chr5-133451642;