Genetic Variant TCF7L1:p.Pro2Leu (chr2-85133689-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_031283.3(TCF7L1):c.5C>T(p.Pro2Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TCF7L1
NM_031283.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.389

Publications

0 publications found

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:

ENSG00000300535 (HGNC:):

ENSG00000300535 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22654149).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031283.3. 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
	TCF7L1	NM_031283.3	MANE Select	c.5C>T	p.Pro2Leu	missense	Exon 1 of 12	NP_112573.1	Q9HCS4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCF7L1	ENST00000282111.4	TSL:1 MANE Select	c.5C>T	p.Pro2Leu	missense	Exon 1 of 12	ENSP00000282111.3	Q9HCS4
TCF7L1	ENST00000922942.1		c.5C>T	p.Pro2Leu	missense	Exon 1 of 12	ENSP00000593001.1
TCF7L1	ENST00000868102.1		c.5C>T	p.Pro2Leu	missense	Exon 1 of 12	ENSP00000538161.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

851282

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

396568

African (AFR)

AF:

0.00

AC:

AN:

16222

American (AMR)

AF:

0.00

AC:

AN:

1738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5768

East Asian (EAS)

AF:

0.00

AC:

AN:

4714

South Asian (SAS)

AF:

0.00

AC:

AN:

17344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

771672

Other (OTH)

AF:

0.00

AC:

AN:

28502

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.23

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.1

PhyloP100

0.39

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.047

Vest4

0.17

MutPred

0.64

Gain of stability (P = 0.0068)

MVP

0.41

MPC

1.2

ClinPred

0.23

GERP RS

1.3

PromoterAI

-0.044

Neutral

(source)

Varity_R

0.42

gMVP

0.56

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over