rs1135728

Variant names:

• chr5-134143082-G-T
• rs1135728
• NM_003202.5:c.1008G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003202.5(TCF7):​c.1008G>T​(p.Trp336Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 5 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7	NM_003202.5	MANE Select	c.1008G>T	p.Trp336Cys	missense	Exon 8 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.1101G>T	p.Trp367Cys	missense	Exon 9 of 11	NP_001333354.1
	TCF7	NM_001346450.2		c.756G>T	p.Trp252Cys	missense	Exon 8 of 10	NP_001333379.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7	ENST00000342854.10	TSL:1 MANE Select	c.1008G>T	p.Trp336Cys	missense	Exon 8 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395023.5	TSL:1	c.663G>T	p.Trp221Cys	missense	Exon 7 of 9	ENSP00000378469.1	P36402-6
	TCF7	ENST00000518915.5	TSL:1	c.663G>T	p.Trp221Cys	missense	Exon 7 of 9	ENSP00000430179.1	P36402-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
PhyloP100		10
PromoterAI		0.0073	Neutral
gMVP		0.99
Mutation Taster		=6/94	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1135728; hg19: chr5-133478773;