Variant 2-85133689-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_031283.3(TCF7L1):c.5C>A(p.Pro2His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000403 in 993,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

TCF7L1
NM_031283.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.389

Variant links:

Genes affected

TCF7L1 (HGNC:11640): (transcription factor 7 like 1) This gene encodes a member of the T cell factor/lymphoid enhancer factor family of transcription factors. These transcription factors are activated by beta catenin, mediate the Wnt signaling pathway and are antagonized by the transforming growth factor beta signaling pathway. The encoded protein contains a high mobility group-box DNA binding domain and participates in the regulation of cell cycle genes and cellular senescence. [provided by RefSeq, Nov 2010]

TCF7L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3280052).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF7L1	NM_031283.3 linkuse as main transcript	c.5C>A	p.Pro2His	missense_variant	1/12	ENST00000282111.4	NP_112573.1
TCF7L1	XM_006712109.3 linkuse as main transcript	c.5C>A	p.Pro2His	missense_variant	1/12		XP_006712172.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF7L1	ENST00000282111.4 linkuse as main transcript	c.5C>A	p.Pro2His	missense_variant	1/12	1	NM_031283.3	ENSP00000282111	P1

Frequencies

GnomAD3 genomes

AF:

0.0000141

AC:

AN:

142010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000310

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000235

AC:

AN:

851282

Hom.:

Cov.:

AF XY:

0.00000252

AC XY:

AN XY:

396568

show subpopulations

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:

0.00000259

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000141

AC:

AN:

142112

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

69072

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000310

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2022

The c.5C>A (p.P2H) alteration is located in exon 1 (coding exon 1) of the TCF7L1 gene. This alteration results from a C to A substitution at nucleotide position 5, causing the proline (P) at amino acid position 2 to be replaced by a histidine (H). 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

0.25

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.42

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.38

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.33

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

1.1

MutationTaster

Benign

0.93

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.84

Vest4

0.26

MutPred

0.64

Loss of catalytic residue at P2 (P = 0.0073);

MVP

0.54

MPC

1.4

ClinPred

0.33

GERP RS

1.3

Varity_R

0.68

gMVP

0.42

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over