Genetic Variant TCF7L1:p.Pro2Arg (chr2-85133689-C-G) – 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>G(p.Pro2Arg) 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 993,292 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000070 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

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=0.22970319).

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>G	p.Pro2Arg	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>G	p.Pro2Arg	missense	Exon 1 of 12	ENSP00000282111.3	Q9HCS4
TCF7L1	ENST00000922942.1		c.5C>G	p.Pro2Arg	missense	Exon 1 of 12	ENSP00000593001.1
TCF7L1	ENST00000868102.1		c.5C>G	p.Pro2Arg	missense	Exon 1 of 12	ENSP00000538161.1

Frequencies

GnomAD3 genomes

AF:

0.00000704

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:

0.000215

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000352

AC:

AN:

851282

Hom.:

Cov.:

AF XY:

0.00000756

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:

0.000115

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:

0.0000351

AC:

AN:

28502

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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:

0.00000704

AC:

AN:

142010

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

68962

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39044

American (AMR)

AF:

0.00

AC:

AN:

14500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3338

East Asian (EAS)

AF:

0.00

AC:

AN:

4972

South Asian (SAS)

AF:

0.000215

AC:

AN:

4642

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7906

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64526

Other (OTH)

AF:

0.00

AC:

AN:

1956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Uncertain

0.42

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.44

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.23

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

1.1

PhyloP100

0.39

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.32

Vest4

0.21

MutPred

0.64

Gain of MoRF binding (P = 2e-04)

MVP

0.52

MPC

1.3

ClinPred

0.17

GERP RS

1.3

PromoterAI

-0.044

Neutral

(source)

Varity_R

0.60

gMVP

0.60

Mutation Taster

=91/9

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