10-112950840-G-T

Variant names:

• chr10-112950840-G-T
• rs373425129
• NM_001367943.1:c.84G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001367943.1(TCF7L2):​c.84G>T​(p.Glu28Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E28Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: TCF7L2 NM_001367943.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.01
• Publications: 0 publications found

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]

TCF7L2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
• intellectual disability

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital glaucoma

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000233547 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25341833).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367943.1. 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
	TCF7L2	NM_001367943.1	MANE Select	c.84G>T	p.Glu28Asp	missense	Exon 1 of 15	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.84G>T	p.Glu28Asp	missense	Exon 1 of 14	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.84G>T	p.Glu28Asp	missense	Exon 1 of 14	NP_110383.2	Q9NQB0-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L2	ENST00000355995.9	TSL:1 MANE Select	c.84G>T	p.Glu28Asp	missense	Exon 1 of 15	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.84G>T	p.Glu28Asp	missense	Exon 1 of 14	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.84G>T	p.Glu28Asp	missense	Exon 1 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.36	N
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.25	T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	1.5	L
PhyloP100		3.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.47
Sift	Benign	0.046	D
Sift4G	Benign	0.11	T
Polyphen		0.011	B
Vest4		0.33
MutPred		0.33		Loss of solvent accessibility (P = 0.1177)
MVP		0.83
MPC		0.69
ClinPred		0.71	D
GERP RS		3.1
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.18
Mutation Taster		=66/34	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: rs373425129; hg19: chr10-114710599;