chr5-134115118-T-C

Variant names:

• chr5-134115118-T-C
• rs1052562972
• NM_003202.5:c.212T>C

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.212T>C​(p.Val71Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000392 in 1,020,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. V71G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.192
• Publications: 1 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=0.0922375).

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.212T>C	p.Val71Ala	missense	Exon 1 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.212T>C	p.Val71Ala	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.212T>C	p.Val71Ala	missense	Exon 1 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395029.5	TSL:5	c.212T>C	p.Val71Ala	missense	Exon 1 of 11	ENSP00000378472.1	B7WNT5
	TCF7	ENST00000851078.1		c.212T>C	p.Val71Ala	missense	Exon 1 of 10	ENSP00000521137.1

Frequencies

GnomAD3 genomes AF: 0.0000140 AC: 2 AN: 143354 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000228 AC: 2 AN: 876860 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 409202

African (AFR) AF: 0.000123 AC: 2 AN: 16258

American (AMR) AF: 0.00 AC: 0 AN: 2170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6482

East Asian (EAS) AF: 0.00 AC: 0 AN: 7490

South Asian (SAS) AF: 0.00 AC: 0 AN: 19164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1860

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 789076

Other (OTH) AF: 0.00 AC: 0 AN: 29544

GnomAD4 genome AF: 0.0000140 AC: 2 AN: 143354 Hom.: 0 Cov.: 31 AF XY: 0.0000143 AC XY: 1 AN XY: 69758

African (AFR) AF: 0.0000514 AC: 2 AN: 38884

American (AMR) AF: 0.00 AC: 0 AN: 14590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 4890

South Asian (SAS) AF: 0.00 AC: 0 AN: 4688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65362

Other (OTH) AF: 0.00 AC: 0 AN: 1998

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.5
DANN	Benign	0.29
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.26	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.092	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.81	L
PhyloP100		0.19
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.26	N
REVEL	Benign	0.21
Sift	Benign	0.98	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.31		Gain of relative solvent accessibility (P = 0.0999)
MVP		0.64
MPC		0.25
ClinPred		0.031	T
GERP RS		-1.2
PromoterAI		0.13	Neutral
gMVP		0.073
Mutation Taster		=90/10	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: rs1052562972; hg19: chr5-133450809;