chr5-134114920-A-G

Variant names:

• chr5-134114920-A-G
• rs1321928612
• NM_003202.5:c.14A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003202.5(TCF7):​c.14A>G​(p.Asp5Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,050,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000069 (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: 1.90
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27114353).

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.14A>G	p.Asp5Gly	missense	Exon 1 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.14A>G	p.Asp5Gly	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.14A>G	p.Asp5Gly	missense	Exon 1 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395029.5	TSL:5	c.14A>G	p.Asp5Gly	missense	Exon 1 of 11	ENSP00000378472.1	B7WNT5
	TCF7	ENST00000851078.1		c.14A>G	p.Asp5Gly	missense	Exon 1 of 10	ENSP00000521137.1

Frequencies

GnomAD3 genomes AF: 0.00000687 AC: 1 AN: 145488 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000679

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: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 17526 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000111 AC: 1 AN: 904648 Hom.: 0 Cov.: 31 AF XY: 0.00000234 AC XY: 1 AN XY: 427754

African (AFR) AF: 0.00 AC: 0 AN: 17264

American (AMR) AF: 0.000191 AC: 1 AN: 5228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7544

East Asian (EAS) AF: 0.00 AC: 0 AN: 7202

South Asian (SAS) AF: 0.00 AC: 0 AN: 27466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1976

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 801988

Other (OTH) AF: 0.00 AC: 0 AN: 30588

GnomAD4 genome AF: 0.00000687 AC: 1 AN: 145488 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 70726

African (AFR) AF: 0.00 AC: 0 AN: 40414

American (AMR) AF: 0.0000679 AC: 1 AN: 14732

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 4954

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65596

Other (OTH) AF: 0.00 AC: 0 AN: 2012

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	0.20
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.068	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.27	T
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	-0.97	N
PhyloP100		1.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.14	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.022	D
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.54		Loss of catalytic residue at D5 (P = 0.1412)
MVP		0.81
MPC		0.27
ClinPred		0.37	T
GERP RS		2.5
PromoterAI		0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
gMVP		0.092
Mutation Taster		=81/19	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: rs1321928612; hg19: chr5-133450611;