5-134115042-C-G

Variant names:

• chr5-134115042-C-G
• rs1010612257
• NM_003202.5:c.136C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003202.5(TCF7):​c.136C>G​(p.Arg46Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 146,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R46C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.527
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3818192).

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.136C>G	p.Arg46Gly	missense	Exon 1 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.136C>G	p.Arg46Gly	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.136C>G	p.Arg46Gly	missense	Exon 1 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395029.5	TSL:5	c.136C>G	p.Arg46Gly	missense	Exon 1 of 11	ENSP00000378472.1	B7WNT5
	TCF7	ENST00000851078.1		c.136C>G	p.Arg46Gly	missense	Exon 1 of 10	ENSP00000521137.1

Frequencies

GnomAD3 genomes AF: 0.00000681 AC: 1 AN: 146928 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000676

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1090468 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 533578

African (AFR) AF: 0.00 AC: 0 AN: 21344

American (AMR) AF: 0.00 AC: 0 AN: 20732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15356

East Asian (EAS) AF: 0.00 AC: 0 AN: 15076

South Asian (SAS) AF: 0.00 AC: 0 AN: 59180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 898984

Other (OTH) AF: 0.00 AC: 0 AN: 39132

GnomAD4 genome AF: 0.00000681 AC: 1 AN: 146928 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 71482

African (AFR) AF: 0.00 AC: 0 AN: 40944

American (AMR) AF: 0.0000676 AC: 1 AN: 14790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5100

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65986

Other (OTH) AF: 0.00 AC: 0 AN: 2026

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Benign	0.89
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	0.54	N
PhyloP100		0.53
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.49
Sift	Benign	0.26	T
Sift4G	Benign	0.28	T
Polyphen		0.024	B
Vest4		0.23
MutPred		0.47		Loss of stability (P = 0.0948)
MVP		0.77
MPC		0.26
ClinPred		0.59	D
GERP RS		3.4
PromoterAI		0.080	Neutral
gMVP		0.15
Mutation Taster		=43/57	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

Other links and lift over

dbSNP: rs1010612257; hg19: chr5-133450733;