rs918278819

Variant names:

• chr5-134115126-G-A
• rs918278819
• NM_003202.5:c.220G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003202.5(TCF7):​c.220G>A​(p.Ala74Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000059 in 1,016,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.103
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15889636).
• BS2: High AC in GnomAd4 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.220G>A	p.Ala74Thr	missense	Exon 1 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.220G>A	p.Ala74Thr	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.220G>A	p.Ala74Thr	missense	Exon 1 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395029.5	TSL:5	c.220G>A	p.Ala74Thr	missense	Exon 1 of 11	ENSP00000378472.1	B7WNT5
	TCF7	ENST00000851078.1		c.220G>A	p.Ala74Thr	missense	Exon 1 of 10	ENSP00000521137.1

Frequencies

GnomAD3 genomes AF: 0.0000342 AC: 5 AN: 146186 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000735

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000115 AC: 1 AN: 870282 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 405042

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

African (AFR) AF: 0.0000609 AC: 1 AN: 16416

American (AMR) AF: 0.00 AC: 0 AN: 1898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6170

East Asian (EAS) AF: 0.00 AC: 0 AN: 7016

South Asian (SAS) AF: 0.00 AC: 0 AN: 17946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1806

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 785376

Other (OTH) AF: 0.00 AC: 0 AN: 29288

⚠️ 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 AF: 0.0000342 AC: 5 AN: 146186 Hom.: 0 Cov.: 31 AF XY: 0.0000563 AC XY: 4 AN XY: 71108

African (AFR) AF: 0.0000735 AC: 3 AN: 40814

American (AMR) AF: 0.00 AC: 0 AN: 14748

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5028

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8416

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

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65726

Other (OTH) AF: 0.00 AC: 0 AN: 2018

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	0.077
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	7.0
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.0	L
PhyloP100		-0.10
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.71	N
REVEL	Benign	0.23
Sift	Benign	0.77	T
Sift4G	Benign	0.57	T
Polyphen		0.0020	B
Vest4		0.072
MutPred		0.33		Gain of glycosylation at A74 (P = 0.0374)
MVP		0.60
MPC		0.20
ClinPred		0.066	T
PromoterAI		0.021	Neutral
gMVP		0.069
Mutation Taster		=97/3	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: rs918278819; hg19: chr5-133450817;