chr10-113126112-G-T

Variant names:

• chr10-113126112-G-T
• rs290494
• NM_001367943.1:c.553-15072G>T

Variant summary

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

The NM_001367943.1(TCF7L2):​c.553-15072G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 124,948 control chromosomes in the GnomAD database, including 28,632 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 0.71 (28632 hom., cov: 25)
  • Failed GnomAD Quality Control
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.09
• Publications: 3 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=-0.53).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1	c.553-15072G>T		intron_variant	Intron 5 of 14	ENST00000355995.9	NP_001354872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF7L2	ENST00000355995.9	c.553-15072G>T		intron_variant	Intron 5 of 14	1	NM_001367943.1	ENSP00000348274.4

Frequencies

GnomAD3 genomes AF: 0.715 AC: 89224 AN: 124846 Hom.: 28599 Cov.: 25

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.742

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.919

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.717

Gnomad NFE AF: 0.616

Gnomad OTH AF: 0.715

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.715 AC: 89304 AN: 124948 Hom.: 28632 Cov.: 25 AF XY: 0.717 AC XY: 43756 AN XY: 61038

African (AFR) AF: 0.824 AC: 32177 AN: 39070

American (AMR) AF: 0.742 AC: 10160 AN: 13694

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 1878 AN: 2792

East Asian (EAS) AF: 0.918 AC: 4640 AN: 5052

South Asian (SAS) AF: 0.738 AC: 3269 AN: 4428

European-Finnish (FIN) AF: 0.618 AC: 4160 AN: 6732

Middle Eastern (MID) AF: 0.704 AC: 190 AN: 270

European-Non Finnish (NFE) AF: 0.616 AC: 31056 AN: 50376

Other (OTH) AF: 0.712 AC: 1268 AN: 1780

Alfa AF: 0.866 Hom.: 9477

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs290494; hg19: chr10-114885871;