chr10-113026395-A-G

Variant names:

• chr10-113026395-A-G
• rs4128597
• NM_001367943.1:c.451-13630A>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.451-13630A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 150,020 control chromosomes in the GnomAD database, including 24,244 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 0.54 (24244 hom., cov: 30)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.395
• Publications: 7 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1	c.451-13630A>G		intron_variant	Intron 4 of 14	ENST00000355995.9	NP_001354872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF7L2	ENST00000355995.9	c.451-13630A>G		intron_variant	Intron 4 of 14	1	NM_001367943.1	ENSP00000348274.4

Frequencies

GnomAD3 genomes AF: 0.540 AC: 80919 AN: 149902 Hom.: 24187 Cov.: 30

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.530

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.0353

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.477

Gnomad OTH AF: 0.549

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

GnomAD4 genome AF: 0.540 AC: 81020 AN: 150020 Hom.: 24244 Cov.: 30 AF XY: 0.530 AC XY: 38772 AN XY: 73156

African (AFR) AF: 0.798 AC: 32906 AN: 41212

American (AMR) AF: 0.413 AC: 6191 AN: 15004

Ashkenazi Jewish (ASJ) AF: 0.431 AC: 1483 AN: 3440

East Asian (EAS) AF: 0.0352 AC: 170 AN: 4836

South Asian (SAS) AF: 0.408 AC: 1923 AN: 4712

European-Finnish (FIN) AF: 0.437 AC: 4476 AN: 10236

Middle Eastern (MID) AF: 0.586 AC: 163 AN: 278

European-Non Finnish (NFE) AF: 0.477 AC: 32114 AN: 67348

Other (OTH) AF: 0.544 AC: 1124 AN: 2068

Alfa AF: 0.525 Hom.: 2894

Bravo AF: 0.540

Asia WGS AF: 0.235 AC: 824 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.6
DANN	Benign	0.64
PhyloP100		-0.40
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: rs4128597; hg19: chr10-114786154;