chr5-134115042-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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 2 ACMG points.

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

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>A	p.Arg46Ser	missense	Exon 1 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.136C>A	p.Arg46Ser	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>A	p.Arg46Ser	missense	Exon 1 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395029.5	TSL:5	c.136C>A	p.Arg46Ser	missense	Exon 1 of 11	ENSP00000378472.1	B7WNT5
	TCF7	ENST00000851078.1		c.136C>A	p.Arg46Ser	missense	Exon 1 of 10	ENSP00000521137.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.00000111 AC: 1 AN: 898984

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
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
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.5	L
PhyloP100		0.53
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.59
Sift	Benign	0.10	T
Sift4G	Benign	0.16	T
Polyphen		0.42	B
Vest4		0.34
MutPred		0.48		Gain of phosphorylation at R46 (P = 0.0065)
MVP		0.85
MPC		0.23
ClinPred		0.86	D
GERP RS		3.4
PromoterAI		0.10	Neutral
gMVP		0.17
Mutation Taster		=50/50

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;