5-134115121-C-G

Variant names:

• chr5-134115121-C-G
• rs1458662519
• NM_003202.5:c.215C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_003202.5(TCF7):​c.215C>G​(p.Pro72Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000573 in 872,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. P72L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.393
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13403416).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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.215C>G	p.Pro72Arg	missense	Exon 1 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.215C>G	p.Pro72Arg	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.215C>G	p.Pro72Arg	missense	Exon 1 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395029.5	TSL:5	c.215C>G	p.Pro72Arg	missense	Exon 1 of 11	ENSP00000378472.1	B7WNT5
	TCF7	ENST00000851078.1		c.215C>G	p.Pro72Arg	missense	Exon 1 of 10	ENSP00000521137.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000573 AC: 5 AN: 872260 Hom.: 0 Cov.: 31 AF XY: 0.00000492 AC XY: 2 AN XY: 406274

African (AFR) AF: 0.00 AC: 0 AN: 16334

American (AMR) AF: 0.00 AC: 0 AN: 1966

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6244

East Asian (EAS) AF: 0.00 AC: 0 AN: 7206

South Asian (SAS) AF: 0.0000546 AC: 1 AN: 18312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1814

European-Non Finnish (NFE) AF: 0.00000509 AC: 4 AN: 786552

Other (OTH) AF: 0.00 AC: 0 AN: 29370

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	0.00052	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.33	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.1	L
PhyloP100		0.39
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.40	N
REVEL	Uncertain	0.35
Sift	Benign	0.11	T
Sift4G	Benign	0.27	T
Polyphen		0.0040	B
Vest4		0.11
MutPred		0.50		Gain of methylation at P72 (P = 0.0078)
MVP		0.66
MPC		0.22
ClinPred		0.068	T
GERP RS		1.3
PromoterAI		0.0036	Neutral
gMVP		0.066
Mutation Taster		=82/18	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: rs1458662519; hg19: chr5-133450812;