Genetic Variant NM_003202.5:c.458C>A (chr5-134138075-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003202.5(TCF7):c.458C>A(p.Pro153His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000804 in 1,603,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P153R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

TCF7
NM_003202.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.97

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06527555).

BS2

High AC in GnomAd4 at 52 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TCF7	NM_003202.5	MANE Select	c.458C>A	p.Pro153His	missense	Exon 4 of 10	NP_003193.2
TCF7	NM_001346425.2		c.458C>A	p.Pro153His	missense	Exon 4 of 11	NP_001333354.1
TCF7	NM_001346450.2		c.113C>A	p.Pro38His	missense	Exon 3 of 10	NP_001333379.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCF7	ENST00000342854.10	TSL:1 MANE Select	c.458C>A	p.Pro153His	missense	Exon 4 of 10	ENSP00000340347.5	P36402-5
TCF7	ENST00000395023.5	TSL:1	c.113C>A	p.Pro38His	missense	Exon 3 of 9	ENSP00000378469.1	P36402-6
TCF7	ENST00000518915.5	TSL:1	c.113C>A	p.Pro38His	missense	Exon 3 of 9	ENSP00000430179.1	P36402-2

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.0000147

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.0000873

AC:

AN:

240518

AF XY:

0.0000615

show subpopulations

Gnomad AFR exome

AF:

0.00101

Gnomad AMR exome

AF:

0.0000628

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.00000912

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000530

AC:

AN:

1451512

Hom.:

Cov.:

AF XY:

0.0000499

AC XY:

AN XY:

722028

show subpopulations

African (AFR)

AF:

0.000938

AC:

AN:

33052

American (AMR)

AF:

0.0000926

AC:

AN:

43200

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25730

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39172

South Asian (SAS)

AF:

0.0000590

AC:

AN:

84742

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.0000262

AC:

AN:

1106660

Other (OTH)

AF:

0.0000834

AC:

AN:

59958

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000342

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.000771

AC:

AN:

41496

American (AMR)

AF:

0.00118

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.000475

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

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:

0.000352

Hom.:

ExAC

AF:

0.000107

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

0.081

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.82

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.065

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.53

PhyloP100

3.0

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.24

REVEL

Uncertain

0.50

Sift

Benign

0.56

Sift4G

Benign

0.64

Polyphen

1.0

Vest4

0.37

MVP

0.97

MPC

0.85

ClinPred

0.071

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

gMVP

0.46

Mutation Taster

=46/54

disease causing

(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