chr5-134115992-C-A

Position:

• chr5-134115992-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000342854.10(TCF7):​c.400C>A​(p.Pro134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,613,646 control chromosomes in the GnomAD database, including 8,276 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P134P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.076 (538 hom., cov: 33)
  • Exomes 𝑓: 0.099 (7738 hom.)
• Consequence: TCF7 ENST00000342854.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015558004).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF7	NM_003202.5	c.400C>A	p.Pro134Thr	missense_variant	3/10	ENST00000342854.10	NP_003193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF7	ENST00000342854.10	c.400C>A	p.Pro134Thr	missense_variant	3/10	1	NM_003202.5	ENSP00000340347	P1

Frequencies

GnomAD3 genomes AF: 0.0761 AC: 11576 AN: 152192 Hom.: 538 Cov.: 33

Gnomad AFR AF: 0.0210

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.133

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0907

GnomAD3 exomes AF: 0.0839 AC: 20937 AN: 249658 Hom.: 1103 AF XY: 0.0831 AC XY: 11248 AN XY: 135414

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.0955

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0256

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0970

GnomAD4 exome AF: 0.0990 AC: 144692 AN: 1461336 Hom.: 7738 Cov.: 33 AF XY: 0.0972 AC XY: 70677 AN XY: 726960

Gnomad4 AFR exome AF: 0.0181

Gnomad4 AMR exome AF: 0.0962

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0275

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.0934

GnomAD4 genome AF: 0.0760 AC: 11578 AN: 152310 Hom.: 538 Cov.: 33 AF XY: 0.0749 AC XY: 5578 AN XY: 74480

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.133

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0257

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.0898

Alfa AF: 0.0907 Hom.: 933

Bravo AF: 0.0745

TwinsUK AF: 0.101 AC: 373

ALSPAC AF: 0.104 AC: 402

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.109 AC: 941

ExAC AF: 0.0816 AC: 9900

Asia WGS AF: 0.0130 AC: 47 AN: 3478

EpiCase AF: 0.106

EpiControl AF: 0.111

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	0.12
DANN	Benign	0.81
DEOGEN2	Benign	0.31	.;T;T;.;.;T;.;.;.;.
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.37	T;T;T;T;T;T;T;.;T;T
MetaRNN	Benign	0.0016	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.69	N;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.62	N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.17	T;T;D;D;D;D;D;T;D;T
Sift4G	Benign	0.25	T;T;D;D;D;D;D;D;D;D
Polyphen		0.0	B;B;.;.;.;.;.;.;.;.
Vest4		0.096
MPC		0.28
ClinPred		0.020	T
GERP RS		-10
gMVP		0.40

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

Other links and lift over

dbSNP: rs5742913; hg19: chr5-133451683;