chr5-134115370-C-T

Variant names:

• chr5-134115370-C-T
• rs762174577
• NM_003202.5:c.299C>T

Variant summary

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

The NM_003202.5(TCF7):​c.299C>T​(p.Pro100Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,776 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P100Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52
• 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.299C>T	p.Pro100Leu	missense	Exon 2 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.299C>T	p.Pro100Leu	missense	Exon 2 of 11	NP_001333354.1
	TCF7	NM_001346450.2		c.-334C>T		upstream_gene	N/A	NP_001333379.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7	ENST00000342854.10	TSL:1 MANE Select	c.299C>T	p.Pro100Leu	missense	Exon 2 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395029.5	TSL:5	c.299C>T	p.Pro100Leu	missense	Exon 2 of 11	ENSP00000378472.1	B7WNT5
	TCF7	ENST00000851078.1		c.299C>T	p.Pro100Leu	missense	Exon 2 of 10	ENSP00000521137.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450776 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720710

⚠️ 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: 33112

American (AMR) AF: 0.00 AC: 0 AN: 43878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25844

East Asian (EAS) AF: 0.00 AC: 0 AN: 39196

South Asian (SAS) AF: 0.00 AC: 0 AN: 84262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107572

Other (OTH) AF: 0.00 AC: 0 AN: 59890

⚠️ 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.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	0.34	N
PhyloP100		2.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.35
Sift	Benign	0.21	T
Sift4G	Benign	0.11	T
Polyphen		0.027	B
Vest4		0.36
MutPred		0.49		Loss of disorder (P = 0.0345)
MVP		0.89
MPC		0.22
ClinPred		0.41	T
GERP RS		1.6
PromoterAI		0.0020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.34
Mutation Taster		=86/14	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: rs762174577; hg19: chr5-133451061;