rs1405525210

Variant names:

• chr5-134115123-G-A
• rs1405525210
• NM_003202.5:c.217G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-134115123-G-A
• chr5-134115123-G-C

Variant summary

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

The NM_003202.5(TCF7):​c.217G>A​(p.Gly73Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 1,019,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.572
• 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=0.31745583).

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.217G>A	p.Gly73Arg	missense	Exon 1 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.217G>A	p.Gly73Arg	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.217G>A	p.Gly73Arg	missense	Exon 1 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395029.5	TSL:5	c.217G>A	p.Gly73Arg	missense	Exon 1 of 11	ENSP00000378472.1	B7WNT5
	TCF7	ENST00000851078.1		c.217G>A	p.Gly73Arg	missense	Exon 1 of 10	ENSP00000521137.1

Frequencies

GnomAD3 genomes AF: 0.00000684 AC: 1 AN: 146122 Hom.: 0 Cov.: 32

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

GnomAD4 exome AF: 0.00000115 AC: 1 AN: 872824 Hom.: 0 Cov.: 31 AF XY: 0.00000246 AC XY: 1 AN XY: 406560

African (AFR) AF: 0.00 AC: 0 AN: 16444

American (AMR) AF: 0.00 AC: 0 AN: 1988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6264

East Asian (EAS) AF: 0.00 AC: 0 AN: 7224

South Asian (SAS) AF: 0.00 AC: 0 AN: 18324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4562

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

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 786814

Other (OTH) AF: 0.00 AC: 0 AN: 29390

GnomAD4 genome AF: 0.00000684 AC: 1 AN: 146232 Hom.: 0 Cov.: 32 AF XY: 0.0000140 AC XY: 1 AN XY: 71182

African (AFR) AF: 0.00 AC: 0 AN: 40866

American (AMR) AF: 0.0000678 AC: 1 AN: 14758

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5008

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65718

Other (OTH) AF: 0.00 AC: 0 AN: 2044

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	0.19
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.34	N
PhyloP100		0.57
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.31	N
REVEL	Uncertain	0.35
Sift	Benign	0.63	T
Sift4G	Benign	0.61	T
Polyphen		1.0	D
Vest4		0.14
MutPred		0.41		Gain of methylation at G73 (P = 0.033)
MVP		0.92
MPC		0.25
ClinPred		0.13	T
PromoterAI		0.017	Neutral
gMVP		0.063
Mutation Taster		=95/5	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: rs1405525210; hg19: chr5-133450814;