rs1315675782

Variant names:

• chr5-134115129-G-T
• rs1315675782
• NM_003202.5:c.223G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_003202.5(TCF7):​c.223G>T​(p.Gly75Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,014,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39409256).
• BS2: High AC in GnomAdExome4 at 13 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.223G>T	p.Gly75Cys	missense	Exon 1 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.223G>T	p.Gly75Cys	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.223G>T	p.Gly75Cys	missense	Exon 1 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395029.5	TSL:5	c.223G>T	p.Gly75Cys	missense	Exon 1 of 11	ENSP00000378472.1	B7WNT5
	TCF7	ENST00000851078.1		c.223G>T	p.Gly75Cys	missense	Exon 1 of 10	ENSP00000521137.1

Frequencies

GnomAD3 genomes AF: 0.00000684 AC: 1 AN: 146142 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000496

GnomAD4 exome AF: 0.0000150 AC: 13 AN: 868298 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 10 AN XY: 403850

African (AFR) AF: 0.0000611 AC: 1 AN: 16374

American (AMR) AF: 0.00 AC: 0 AN: 1866

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6106

East Asian (EAS) AF: 0.00 AC: 0 AN: 6830

South Asian (SAS) AF: 0.00 AC: 0 AN: 17538

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1792

European-Non Finnish (NFE) AF: 0.0000153 AC: 12 AN: 784386

Other (OTH) AF: 0.00 AC: 0 AN: 29198

GnomAD4 genome AF: 0.00000684 AC: 1 AN: 146142 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 71066

African (AFR) AF: 0.00 AC: 0 AN: 40776

American (AMR) AF: 0.00 AC: 0 AN: 14740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3392

East Asian (EAS) AF: 0.00 AC: 0 AN: 5040

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65740

Other (OTH) AF: 0.000496 AC: 1 AN: 2016

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

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	0.17
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.41
Sift	Benign	0.042	D
Sift4G	Uncertain	0.052	T
Polyphen		0.55	P
Vest4		0.22
MutPred		0.46		Loss of catalytic residue at A74 (P = 0.1482)
MVP		0.92
MPC		0.22
ClinPred		0.40	T
GERP RS		3.2
PromoterAI		0.12	Neutral
gMVP		0.10
Mutation Taster		=89/11	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: rs1315675782; hg19: chr5-133450820;