Genetic Variant TCF7:p.Ala78Thr (chr5-134115138-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003202.5(TCF7):c.232G>A(p.Ala78Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,012,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

TCF7
NM_003202.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09050432).

BS2

High AC in GnomAd4 at 40 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003202.5. 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
	TCF7	NM_003202.5	MANE Select	c.232G>A	p.Ala78Thr	missense	Exon 1 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.232G>A	p.Ala78Thr	missense	Exon 1 of 11	NP_001333354.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCF7	ENST00000342854.10	TSL:1 MANE Select	c.232G>A	p.Ala78Thr	missense	Exon 1 of 10	ENSP00000340347.5	P36402-5
TCF7	ENST00000395029.5	TSL:5	c.232G>A	p.Ala78Thr	missense	Exon 1 of 11	ENSP00000378472.1	B7WNT5
TCF7	ENST00000851078.1		c.232G>A	p.Ala78Thr	missense	Exon 1 of 10	ENSP00000521137.1

Frequencies

GnomAD3 genomes

AF:

0.000274

AC:

AN:

146092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00913

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000122

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

148

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

GnomAD4 exome

AF:

0.000156

AC:

135

AN:

866322

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

402832

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16390

American (AMR)

AF:

0.00

AC:

AN:

1858

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

AN:

6028

East Asian (EAS)

AF:

0.00

AC:

AN:

6390

South Asian (SAS)

AF:

0.00

AC:

AN:

17320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1790

European-Non Finnish (NFE)

AF:

0.0000498

AC:

AN:

783344

Other (OTH)

AF:

0.000925

AC:

AN:

29184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000274

AC:

AN:

146092

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

AN XY:

71026

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40718

American (AMR)

AF:

0.00

AC:

AN:

14734

Ashkenazi Jewish (ASJ)

AF:

0.00913

AC:

AN:

3394

East Asian (EAS)

AF:

0.00

AC:

AN:

5026

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.000122

AC:

AN:

65718

Other (OTH)

AF:

0.00

AC:

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000498

Hom.:

Bravo

AF:

0.000291

ExAC

AF:

0.000822

AC:

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

Benign

0.076

BayesDel_addAF

Benign

-0.0048

BayesDel_noAF

Benign

-0.24

CADD

Benign

9.6

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.22

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.091

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

0.90

PhyloP100

1.0

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.35

REVEL

Uncertain

0.36

Sift

Benign

0.52

Sift4G

Benign

0.43

Polyphen

0.0020

Vest4

0.031

MutPred

0.51

Gain of glycosylation at A78 (P = 0.0295)

MVP

0.78

MPC

0.20

ClinPred

0.067

GERP RS

2.9

PromoterAI

-0.048

Neutral

(source)

gMVP

0.081

Mutation Taster

=96/4

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

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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