Genetic Variant TCF7L1:p.Pro2His (chr2-85133689-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

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>A	p.Pro2His	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>A	p.Pro2His	missense	Exon 1 of 12	ENSP00000282111.3	Q9HCS4
TCF7L1	ENST00000922942.1		c.5C>A	p.Pro2His	missense	Exon 1 of 12	ENSP00000593001.1
TCF7L1	ENST00000868102.1		c.5C>A	p.Pro2His	missense	Exon 1 of 12	ENSP00000538161.1

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

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:

0.00000259

AC:

AN:

771672

Other (OTH)

AF:

0.00

AC:

AN:

28502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000141

AC:

AN:

142112

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

69072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39150

American (AMR)

AF:

0.00

AC:

AN:

14520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3338

East Asian (EAS)

AF:

0.00

AC:

AN:

4956

South Asian (SAS)

AF:

0.00

AC:

AN:

4638

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7906

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.0000310

AC:

AN:

64516

Other (OTH)

AF:

0.00

AC:

AN:

1978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

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

PhyloP100

0.39

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

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.68

gMVP

0.42

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over