10-112950883-G-A

Variant names:

• chr10-112950883-G-A
• NM_001367943.1:c.127G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001367943.1(TCF7L2):​c.127G>A​(p.Asp43Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: TCF7L2 NM_001367943.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.94

Genes affected

TCF7L2 (HGNC:11641): (transcription factor 7 like 2) This gene encodes a high mobility group (HMG) box-containing transcription factor that plays a key role in the Wnt signaling pathway. The protein has been implicated in blood glucose homeostasis. Genetic variants of this gene are associated with increased risk of type 2 diabetes. Several transcript variants encoding multiple different isoforms have been found for this gene.[provided by RefSeq, Oct 2010]

ENSG00000233547 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.849

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1	c.127G>A	p.Asp43Asn	missense_variant	Exon 1 of 15	ENST00000355995.9	NP_001354872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF7L2	ENST00000355995.9	c.127G>A	p.Asp43Asn	missense_variant	Exon 1 of 15	1	NM_001367943.1	ENSP00000348274.4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TCF7L2: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T;D;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Benign	0.62	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	.;.;M;M;.;M;M;M;M;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.5	D;D;D;D;D;.;D;D;D;D;D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0010	D;D;D;D;D;.;D;D;T;D;D;.
Sift4G	Benign	0.085	T;T;T;T;T;T;T;T;T;D;T;T
Polyphen		1.0, 0.99, 1.0	.;D;.;.;.;D;.;.;.;.;D;.
Vest4		0.60
MutPred		0.56		Gain of methylation at K45 (P = 0.0652);Gain of methylation at K45 (P = 0.0652);Gain of methylation at K45 (P = 0.0652);Gain of methylation at K45 (P = 0.0652);Gain of methylation at K45 (P = 0.0652);Gain of methylation at K45 (P = 0.0652);Gain of methylation at K45 (P = 0.0652);Gain of methylation at K45 (P = 0.0652);Gain of methylation at K45 (P = 0.0652);Gain of methylation at K45 (P = 0.0652);Gain of methylation at K45 (P = 0.0652);Gain of methylation at K45 (P = 0.0652);
MVP		0.98
MPC		1.6
ClinPred		0.99	D
GERP RS		3.1
Varity_R		0.90
gMVP		0.58

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-114710642;