rs1237423250

Variant names:

• chr5-134114943-G-A
• rs1237423250
• NM_003202.5:c.37G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-134114943-G-A
• chr5-134114943-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.37G>A​(p.Gly13Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 968,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G13R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: TCF7 NM_003202.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.49
• 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=0.32500273).

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.37G>A	p.Gly13Ser	missense	Exon 1 of 10	NP_003193.2
	TCF7	NM_001346425.2		c.37G>A	p.Gly13Ser	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.37G>A	p.Gly13Ser	missense	Exon 1 of 10	ENSP00000340347.5	P36402-5
	TCF7	ENST00000395029.5	TSL:5	c.37G>A	p.Gly13Ser	missense	Exon 1 of 11	ENSP00000378472.1	B7WNT5
	TCF7	ENST00000851078.1		c.37G>A	p.Gly13Ser	missense	Exon 1 of 10	ENSP00000521137.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000443 AC: 2 AN: 45102 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000239

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: 0.00000310 AC: 3 AN: 968710 Hom.: 0 Cov.: 31 AF XY: 0.00000215 AC XY: 1 AN XY: 465234

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

African (AFR) AF: 0.00 AC: 0 AN: 18580

American (AMR) AF: 0.00 AC: 0 AN: 10282

Ashkenazi Jewish (ASJ) AF: 0.0000916 AC: 1 AN: 10918

East Asian (EAS) AF: 0.00 AC: 0 AN: 9370

South Asian (SAS) AF: 0.0000248 AC: 1 AN: 40250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2192

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 833826

Other (OTH) AF: 0.00 AC: 0 AN: 33398

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0561929), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.33	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.2	L
PhyloP100		4.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.18	N
REVEL	Uncertain	0.43
Sift	Benign	0.16	T
Sift4G	Benign	0.34	T
Polyphen		0.0070	B
Vest4		0.26
MutPred		0.63		Gain of phosphorylation at G13 (P = 0.0069)
MVP		0.87
MPC		0.20
ClinPred		0.093	T
GERP RS		2.4
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
gMVP		0.063
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: rs1237423250; hg19: chr5-133450634;