10-113147296-A-G

Variant names:

• chr10-113147296-A-G
• rs290489
• NM_001367943.1:c.875+1199A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001367943.1(TCF7L2):​c.875+1199A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 152,098 control chromosomes in the GnomAD database, including 6,301 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.28 (6301 hom., cov: 32)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.18
• Publications: 21 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 Submitted by: G2P
• intellectual disability

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

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L2	NM_001367943.1	MANE Select	c.875+1199A>G		intron	N/A	NP_001354872.1
	TCF7L2	NM_001146274.2		c.875+1199A>G		intron	N/A	NP_001139746.1
	TCF7L2	NM_030756.5		c.806+1199A>G		intron	N/A	NP_110383.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L2	ENST00000355995.9	TSL:1 MANE Select	c.875+1199A>G		intron	N/A	ENSP00000348274.4
	TCF7L2	ENST00000627217.3	TSL:1	c.875+1199A>G		intron	N/A	ENSP00000486891.1
	TCF7L2	ENST00000369397.8	TSL:1	c.806+1199A>G		intron	N/A	ENSP00000358404.4

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41878 AN: 151980 Hom.: 6297 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.291

Gnomad AMR AF: 0.243

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.285

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.276 AC: 41907 AN: 152098 Hom.: 6301 Cov.: 32 AF XY: 0.279 AC XY: 20759 AN XY: 74352

African (AFR) AF: 0.282 AC: 11693 AN: 41486

American (AMR) AF: 0.243 AC: 3715 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1088 AN: 3470

East Asian (EAS) AF: 0.687 AC: 3552 AN: 5170

South Asian (SAS) AF: 0.389 AC: 1872 AN: 4810

European-Finnish (FIN) AF: 0.261 AC: 2763 AN: 10574

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16265 AN: 67990

Other (OTH) AF: 0.285 AC: 602 AN: 2114

Alfa AF: 0.259 Hom.: 7347

Bravo AF: 0.276

Asia WGS AF: 0.473 AC: 1641 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.0
DANN	Benign	0.78
PhyloP100		2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs290489; hg19: chr10-114907055;