5-134115138-G-T

Variant names:

• chr5-134115138-G-T
• rs757624060
• NM_003202.5:c.232G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003202.5(TCF7):​c.232G>T​(p.Ala78Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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. A78T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24356213).

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.232G>T	p.Ala78Ser	missense	Exon 1 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.232G>T	p.Ala78Ser	missense	Exon 1 of 11	NP_001333354.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7	ENST00000342854.10	TSL:1 MANE Select	c.232G>T	p.Ala78Ser	missense	Exon 1 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395029.5	TSL:5	c.232G>T	p.Ala78Ser	missense	Exon 1 of 11	ENSP00000378472.1	B7WNT5
	TCF7	ENST00000851078.1		c.232G>T	p.Ala78Ser	missense	Exon 1 of 10	ENSP00000521137.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 866322 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 402832

African (AFR) AF: 0.00 AC: 0 AN: 16390

American (AMR) AF: 0.00 AC: 0 AN: 1858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6028

East Asian (EAS) AF: 0.00 AC: 0 AN: 6390

South Asian (SAS) AF: 0.00 AC: 0 AN: 17320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1790

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 783344

Other (OTH) AF: 0.00 AC: 0 AN: 29184

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	6.5
DANN	Benign	0.87
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.39	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	0.0	N
PhyloP100		1.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.41	N
REVEL	Uncertain	0.36
Sift	Benign	1.0	T
Sift4G	Benign	0.48	T
Polyphen		0.017	B
Vest4		0.056
MutPred		0.49		Gain of glycosylation at A78 (P = 0.0065)
MVP		0.72
MPC		0.19
ClinPred		0.052	T
GERP RS		2.9
PromoterAI		-0.11	Neutral
gMVP		0.091
Mutation Taster		=96/4	polymorphism

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: rs757624060; hg19: chr5-133450829;