Genetic Variant TCF7:p.Pro72Leu (chr5-134115121-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

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

The NM_003202.5(TCF7):c.215C>T(p.Pro72Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000324 in 1,017,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict 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: 0.000036 ( 0 hom. )

Consequence

TCF7
NM_003202.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.393

Variant links:

Genes affected

TCF7 (HGNC:11639): (transcription factor 7) This gene encodes a member of the T-cell factor/lymphoid enhancer-binding factor family of high mobility group (HMG) box transcriptional activators. This gene is expressed predominantly in T-cells and plays a critical role in natural killer cell and innate lymphoid cell development. The encoded protein forms a complex with beta-catenin and activates transcription through a Wnt/beta-catenin signaling pathway. Mice with a knockout of this gene are viable and fertile, but display a block in T-lymphocyte differentiation. Alternative splicing results in multiple transcript variants. Naturally-occurring isoforms lacking the N-terminal beta-catenin interaction domain may act as dominant negative regulators of Wnt signaling. [provided by RefSeq, Oct 2016]

TCF7 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=0.15483817).

BS2

High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7	NM_003202.5 link	c.215C>T	p.Pro72Leu	missense_variant	Exon 1 of 10	ENST00000342854.10	NP_003193.2	P36402-5B3KQ75

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TCF7	ENST00000342854.10 link	c.215C>T	p.Pro72Leu	missense_variant	Exon 1 of 10	1	NM_003202.5	ENSP00000340347.5	P36402-5
TCF7	ENST00000395029.5 link	c.215C>T	p.Pro72Leu	missense_variant	Exon 1 of 11	5		ENSP00000378472.1	B7WNT5
TCF7	ENST00000518887.5 link	c.-296C>T		upstream_gene_variant		2		ENSP00000430617.1	E5RJ51
TCF7	ENST00000522653.5 link	n.-231C>T		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000137

AC:

AN:

145556

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000494

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000355

AC:

AN:

872260

Hom.:

Cov.:

AF XY:

0.0000246

AC XY:

AN XY:

406274

show subpopulations

Gnomad4 AFR exome

AF:

0.0000612

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000381

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000137

AC:

AN:

145556

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70796

show subpopulations

Gnomad4 AFR

AF:

0.0000494

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.215C>T (p.P72L) alteration is located in exon 1 (coding exon 1) of the TCF7 gene. This alteration results from a C to T substitution at nucleotide position 215, causing the proline (P) at amino acid position 72 to be replaced by a leucine (L). 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

BayesDel_addAF

Benign

-0.0092

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

.;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.49

T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.15

T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Benign

1.4

L;.

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.082

T;T

Sift4G

Uncertain

0.040

D;D

Polyphen

0.0030

B;.

Vest4

0.14

MutPred

0.43

Gain of stability (P = 0.0848);Gain of stability (P = 0.0848);

MVP

0.73

MPC

0.21

ClinPred

0.12

GERP RS

1.3

gMVP

0.091

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