10-113014168-A-G

Variant names:

• chr10-113014168-A-G
• rs7904519
• NM_001367943.1:c.451-25857A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001367943.1(TCF7L2):​c.451-25857A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 151,974 control chromosomes in the GnomAD database, including 24,623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.54 (24623 hom., cov: 33)
• Consequence: TCF7L2 NM_001367943.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.19
• Publications: 82 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 10-113014168-A-G is Benign according to our data. Variant chr10-113014168-A-G is described in ClinVar as Benign. ClinVar VariationId is 225819.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1	c.451-25857A>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.451-25857A>G		intron_variant	Intron 4 of 14	1	NM_001367943.1	ENSP00000348274.4

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81499 AN: 151856 Hom.: 24564 Cov.: 33

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.0336

Gnomad SAS AF: 0.400

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.541

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

GnomAD4 genome AF: 0.537 AC: 81603 AN: 151974 Hom.: 24623 Cov.: 33 AF XY: 0.526 AC XY: 39050 AN XY: 74294

African (AFR) AF: 0.806 AC: 33438 AN: 41470

American (AMR) AF: 0.407 AC: 6212 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1462 AN: 3464

East Asian (EAS) AF: 0.0334 AC: 173 AN: 5174

South Asian (SAS) AF: 0.401 AC: 1931 AN: 4816

European-Finnish (FIN) AF: 0.426 AC: 4497 AN: 10566

Middle Eastern (MID) AF: 0.568 AC: 166 AN: 292

European-Non Finnish (NFE) AF: 0.473 AC: 32125 AN: 67908

Other (OTH) AF: 0.536 AC: 1130 AN: 2110

Alfa AF: 0.487 Hom.: 42977

Bravo AF: 0.543

Asia WGS AF: 0.235 AC: 824 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.17
DANN	Benign	0.27
PhyloP100		-1.2
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: rs7904519; hg19: chr10-114773927;