10-113066054-A-G

Variant names:

• chr10-113066054-A-G
• rs7100388
• NM_001367943.1:c.552+25928A>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.552+25928A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 152,182 control chromosomes in the GnomAD database, including 1,026 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 0.11 (1026 hom., cov: 33)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185
• Publications: 6 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=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1	c.552+25928A>G		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.552+25928A>G		intron_variant	Intron 5 of 14	1	NM_001367943.1	ENSP00000348274.4

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16611 AN: 152064 Hom.: 1020 Cov.: 33

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0721

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.0498

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0925

Gnomad OTH AF: 0.108

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

GnomAD4 genome AF: 0.109 AC: 16645 AN: 152182 Hom.: 1026 Cov.: 33 AF XY: 0.108 AC XY: 8034 AN XY: 74414

African (AFR) AF: 0.145 AC: 6039 AN: 41522

American (AMR) AF: 0.106 AC: 1617 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 459 AN: 3466

East Asian (EAS) AF: 0.0712 AC: 368 AN: 5172

South Asian (SAS) AF: 0.219 AC: 1051 AN: 4810

European-Finnish (FIN) AF: 0.0498 AC: 528 AN: 10610

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0925 AC: 6289 AN: 68010

Other (OTH) AF: 0.115 AC: 244 AN: 2114

Alfa AF: 0.0991 Hom.: 2528

Bravo AF: 0.110

Asia WGS AF: 0.205 AC: 716 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.9
DANN	Benign	0.83
PhyloP100		0.18
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: rs7100388; hg19: chr10-114825813;