Variant chr2-85133727-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_031283.3(TCF7L1):c.43A>G(p.Ser15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,180,392 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00059 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TCF7L1
NM_031283.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.41

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.083673626).

BS2

High AC in GnomAd4 at 86 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF7L1	NM_031283.3 linkuse as main transcript	c.43A>G	p.Ser15Gly	missense_variant	1/12	ENST00000282111.4	NP_112573.1	Q9HCS4
TCF7L1	XM_006712109.3 linkuse as main transcript	c.43A>G	p.Ser15Gly	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.43A>G	p.Ser15Gly	missense_variant	1/12	1	NM_031283.3	ENSP00000282111.3		Q9HCS4

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

145190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00209

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:

0.0000152

Gnomad OTH

AF:

0.000499

GnomAD4 exome

AF:

0.000116

AC:

120

AN:

1035096

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

489644

show subpopulations

Gnomad4 AFR exome

AF:

0.00393

Gnomad4 AMR exome

AF:

0.000143

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000430

Gnomad4 SAS exome

AF:

0.0000523

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000236

Gnomad4 OTH exome

AF:

0.000246

GnomAD4 genome

AF:

0.000592

AC:

AN:

145296

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

70804

show subpopulations

Gnomad4 AFR

AF:

0.00211

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:

0.0000152

Gnomad4 OTH

AF:

0.000494

Alfa

AF:

0.000356

Hom.:

Bravo

AF:

0.000620

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

Dec 19, 2022

The c.43A>G (p.S15G) alteration is located in exon 1 (coding exon 1) of the TCF7L1 gene. This alteration results from a A to G substitution at nucleotide position 43, causing the serine (S) at amino acid position 15 to be replaced by a glycine (G). 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

0.047

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.40

DEOGEN2

Benign

0.083

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.18

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.084

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

-0.34

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.14

REVEL

Uncertain

0.30

Sift

Benign

0.26

Sift4G

Benign

0.38

Polyphen

0.0

Vest4

0.17

MutPred

0.35

Loss of phosphorylation at S15 (P = 0.0011);

MVP

0.68

MPC

1.1

ClinPred

0.11

GERP RS

0.82

Varity_R

0.058

gMVP

0.33

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