rs249611

Variant names:

• chr5-134128966-T-C
• rs249611
• NM_003202.5:c.442-9093T>C

Variant summary

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

The NM_003202.5(TCF7):​c.442-9093T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.088 in 152,226 control chromosomes in the GnomAD database, including 1,063 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.088 (1063 hom., cov: 33)
• Consequence: TCF7 NM_003202.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.171
• Publications: 7 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 (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7	NM_003202.5	c.442-9093T>C		intron_variant	Intron 3 of 9	ENST00000342854.10	NP_003193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF7	ENST00000342854.10	c.442-9093T>C		intron_variant	Intron 3 of 9	1	NM_003202.5	ENSP00000340347.5

Frequencies

GnomAD3 genomes AF: 0.0880 AC: 13382 AN: 152108 Hom.: 1059 Cov.: 33

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0832

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0894

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0842

Gnomad OTH AF: 0.0777

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0880 AC: 13395 AN: 152226 Hom.: 1063 Cov.: 33 AF XY: 0.0923 AC XY: 6871 AN XY: 74434

African (AFR) AF: 0.0224 AC: 929 AN: 41556

American (AMR) AF: 0.178 AC: 2718 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0832 AC: 289 AN: 3472

East Asian (EAS) AF: 0.394 AC: 2037 AN: 5170

South Asian (SAS) AF: 0.111 AC: 533 AN: 4822

European-Finnish (FIN) AF: 0.0894 AC: 948 AN: 10606

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0842 AC: 5722 AN: 67992

Other (OTH) AF: 0.0783 AC: 165 AN: 2106

Alfa AF: 0.0915 Hom.: 645

Bravo AF: 0.0945

Asia WGS AF: 0.197 AC: 683 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.5
DANN	Benign	0.57
PhyloP100		0.17
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: rs249611; hg19: chr5-133464657;