NM_003202.5:c.136C>A

Variant names:

• chr5-134115042-C-A
• NM_003202.5:c.136C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003202.5(TCF7):​c.136C>A​(p.Arg46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000917 in 1,090,468 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R46C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.527

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7	NM_003202.5	c.136C>A	p.Arg46Ser	missense_variant	Exon 1 of 10	ENST00000342854.10	NP_003193.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF7	ENST00000342854.10	c.136C>A	p.Arg46Ser	missense_variant	Exon 1 of 10	1	NM_003202.5	ENSP00000340347.5
TCF7	ENST00000395029.5	c.136C>A	p.Arg46Ser	missense_variant	Exon 1 of 11	5		ENSP00000378472.1
TCF7	ENST00000518887.5	c.-375C>A		upstream_gene_variant		2		ENSP00000430617.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.17e-7 AC: 1 AN: 1090468 Hom.: 0 Cov.: 31 AF XY: 0.00000187 AC XY: 1 AN XY: 533578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-2.5	D;N
REVEL	Uncertain	0.59
Sift	Benign	0.10	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.42	B;.
Vest4		0.34
MutPred		0.48		Gain of phosphorylation at R46 (P = 0.0065);Gain of phosphorylation at R46 (P = 0.0065);
MVP		0.85
MPC		0.23
ClinPred		0.86	D
GERP RS		3.4
gMVP		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-133450733;