Genetic Variant TCF7L1:p.Glu37Lys (chr2-85133793-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_031283.3(TCF7L1):c.109G>A(p.Glu37Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000081 in 1,234,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.1e-7 ( 0 hom. )

Consequence

TCF7L1
NM_031283.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.74

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 Gene-Disease associations (from GenCC):

combined pituitary hormone deficiencies, genetic form
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

TCF7L1 links:

ENSG00000300535 (HGNC:):

ENSG00000300535 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

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.109G>A	p.Glu37Lys	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.109G>A	p.Glu37Lys	missense	Exon 1 of 12	ENSP00000282111.3	Q9HCS4
TCF7L1	ENST00000922942.1		c.109G>A	p.Glu37Lys	missense	Exon 1 of 12	ENSP00000593001.1
TCF7L1	ENST00000868102.1		c.109G>A	p.Glu37Lys	missense	Exon 1 of 12	ENSP00000538161.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.10e-7

AC:

AN:

1234844

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

602606

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25192

American (AMR)

AF:

0.00

AC:

AN:

17870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19506

East Asian (EAS)

AF:

0.00

AC:

AN:

27668

South Asian (SAS)

AF:

0.00

AC:

AN:

54680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4226

European-Non Finnish (NFE)

AF:

0.00000100

AC:

AN:

996356

Other (OTH)

AF:

0.00

AC:

AN:

49764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

ClinVar submissions

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

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.3

PhyloP100

6.7

PrimateAI

Pathogenic

0.97

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.52

MutPred

0.71

Gain of ubiquitination at E37 (P = 0.0025)

MVP

0.93

MPC

2.6

ClinPred

1.0

GERP RS

3.8

PromoterAI

0.027

Neutral

(source)

Varity_R

0.84

gMVP

0.33

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over