rs30489

Positions:

• chr5-134145776-G-A

Variant summary

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

The ENST00000518915.5(TCF7):​c.766G>A​(p.Gly256Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0979 in 1,613,706 control chromosomes in the GnomAD database, including 11,037 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.087 (1055 hom., cov: 32)
  • Exomes 𝑓: 0.099 (9982 hom.)
• Consequence: TCF7 ENST00000518915.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.241

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=0.0020443797).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF7	NM_003202.5	c.1076-448G>A		intron_variant		ENST00000342854.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF7	ENST00000342854.10	c.1076-448G>A		intron_variant		1	NM_003202.5	P1

Frequencies

GnomAD3 genomes AF: 0.0869 AC: 13210 AN: 152088 Hom.: 1051 Cov.: 32

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0831

Gnomad EAS AF: 0.390

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0893

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0837

Gnomad OTH AF: 0.0769

GnomAD3 exomes AF: 0.133 AC: 33112 AN: 249006 Hom.: 3652 AF XY: 0.126 AC XY: 16983 AN XY: 135096

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.283

Gnomad ASJ exome AF: 0.0810

Gnomad EAS exome AF: 0.394

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0879

Gnomad NFE exome AF: 0.0837

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0990 AC: 144724 AN: 1461500 Hom.: 9982 Cov.: 32 AF XY: 0.0984 AC XY: 71539 AN XY: 727030

Gnomad4 AFR exome AF: 0.0165

Gnomad4 AMR exome AF: 0.270

Gnomad4 ASJ exome AF: 0.0797

Gnomad4 EAS exome AF: 0.385

Gnomad4 SAS exome AF: 0.104

Gnomad4 FIN exome AF: 0.0843

Gnomad4 NFE exome AF: 0.0853

Gnomad4 OTH exome AF: 0.100

GnomAD4 genome AF: 0.0869 AC: 13220 AN: 152206 Hom.: 1055 Cov.: 32 AF XY: 0.0911 AC XY: 6782 AN XY: 74408

Gnomad4 AFR AF: 0.0201

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.0831

Gnomad4 EAS AF: 0.390

Gnomad4 SAS AF: 0.109

Gnomad4 FIN AF: 0.0893

Gnomad4 NFE AF: 0.0837

Gnomad4 OTH AF: 0.0775

Alfa AF: 0.0935 Hom.: 2209

Bravo AF: 0.0933

TwinsUK AF: 0.0965 AC: 358

ALSPAC AF: 0.0841 AC: 324

ESP6500AA AF: 0.0247 AC: 97

ESP6500EA AF: 0.0833 AC: 692

ExAC AF: 0.122 AC: 14812

Asia WGS AF: 0.196 AC: 681 AN: 3478

EpiCase AF: 0.0896

EpiControl AF: 0.0883

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	0.52
DANN	Uncertain	0.99
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.15	T
Vest4		0.021
ClinPred		0.015	T
GERP RS		-2.6

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: rs30489; hg19: chr5-133481467; COSMIC: COSV58658450; COSMIC: COSV58658450;