rs5742913

Variant names:

• chr5-134115992-C-A
• rs5742913
• NM_003202.5:c.400C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-134115992-C-A
• chr5-134115992-C-G
• chr5-134115992-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003202.5(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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P134H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.076 (538 hom., cov: 33)
  • Exomes 𝑓: 0.099 (7738 hom.)
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 35 publications found

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

Our verdict: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7	NM_003202.5	MANE Select	c.400C>A	p.Pro134Thr	missense	Exon 3 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.400C>A	p.Pro134Thr	missense	Exon 3 of 11	NP_001333354.1
	TCF7	NM_001346450.2		c.55C>A	p.Pro19Thr	missense	Exon 2 of 10	NP_001333379.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7	ENST00000342854.10	TSL:1 MANE Select	c.400C>A	p.Pro134Thr	missense	Exon 3 of 10	ENSP00000340347.5
	TCF7	ENST00000395023.5	TSL:1	c.55C>A	p.Pro19Thr	missense	Exon 2 of 9	ENSP00000378469.1
	TCF7	ENST00000518915.5	TSL:1	c.55C>A	p.Pro19Thr	missense	Exon 2 of 9	ENSP00000430179.1

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

GnomAD2 exomes AF: 0.0839 AC: 20937 AN: 249658 AF XY: 0.0831

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 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

African (AFR) AF: 0.0181 AC: 607 AN: 33476

American (AMR) AF: 0.0962 AC: 4301 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3409 AN: 26136

East Asian (EAS) AF: 0.000605 AC: 24 AN: 39700

South Asian (SAS) AF: 0.0275 AC: 2368 AN: 86258

European-Finnish (FIN) AF: 0.104 AC: 5498 AN: 52958

Middle Eastern (MID) AF: 0.0905 AC: 522 AN: 5768

European-Non Finnish (NFE) AF: 0.110 AC: 122325 AN: 1111954

Other (OTH) AF: 0.0934 AC: 5638 AN: 60376

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

African (AFR) AF: 0.0209 AC: 870 AN: 41574

American (AMR) AF: 0.101 AC: 1542 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 461 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4830

European-Finnish (FIN) AF: 0.112 AC: 1186 AN: 10616

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.104 AC: 7087 AN: 68008

Other (OTH) AF: 0.0898 AC: 190 AN: 2116

Alfa AF: 0.0886 Hom.: 1461

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	0.12
DANN	Benign	0.81
DEOGEN2	Benign	0.31	T
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.7
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0016	T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.69	N
PhyloP100		-1.7
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.38
Sift	Benign	0.17	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.096
MPC		0.28
ClinPred		0.020	T
GERP RS		-10
PromoterAI		-0.056	Neutral
gMVP		0.40
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5742913; hg19: chr5-133451683;