chr10-112950449-G-GT

Variant names:

• chr10-112950449-G-GT
• rs74804400
• NM_001367943.1:c.-294dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001367943.1(TCF7L2):​c.-294dupT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (2955 hom., cov: 17)
  • Exomes 𝑓: 0.16 (30 hom.)
• Consequence: TCF7L2 NM_001367943.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.385
• Publications: 1 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, STRONG Submitted by: G2P, PanelApp Australia
• intellectual disability

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

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000233547 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 10-112950449-G-GT is Benign according to our data. Variant chr10-112950449-G-GT is described in ClinVar as Benign. ClinVar VariationId is 1274713.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.279 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L2	NM_001367943.1	MANE Select	c.-294dupT		5_prime_UTR	Exon 1 of 15	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.-294dupT		5_prime_UTR	Exon 1 of 14	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.-294dupT		5_prime_UTR	Exon 1 of 14	NP_110383.2	Q9NQB0-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCF7L2	ENST00000355995.9	TSL:1 MANE Select	c.-294dupT		5_prime_UTR	Exon 1 of 15	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.-294dupT		5_prime_UTR	Exon 1 of 14	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.-294dupT		5_prime_UTR	Exon 1 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes AF: 0.208 AC: 25078 AN: 120542 Hom.: 2953 Cov.: 17

Gnomad AFR AF: 0.0881

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.0498

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.226

GnomAD4 exome AF: 0.157 AC: 11337 AN: 72310 Hom.: 30 Cov.: 0 AF XY: 0.153 AC XY: 5536 AN XY: 36170

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.112 AC: 259 AN: 2312

American (AMR) AF: 0.156 AC: 364 AN: 2334

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 627 AN: 3300

East Asian (EAS) AF: 0.0906 AC: 707 AN: 7806

South Asian (SAS) AF: 0.0878 AC: 551 AN: 6276

European-Finnish (FIN) AF: 0.0694 AC: 104 AN: 1498

Middle Eastern (MID) AF: 0.200 AC: 70 AN: 350

European-Non Finnish (NFE) AF: 0.179 AC: 7777 AN: 43358

Other (OTH) AF: 0.173 AC: 878 AN: 5076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.208 AC: 25078 AN: 120552 Hom.: 2955 Cov.: 17 AF XY: 0.200 AC XY: 11394 AN XY: 56886

African (AFR) AF: 0.0880 AC: 2847 AN: 32336

American (AMR) AF: 0.240 AC: 2744 AN: 11426

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 762 AN: 3088

East Asian (EAS) AF: 0.0497 AC: 204 AN: 4104

South Asian (SAS) AF: 0.160 AC: 554 AN: 3454

European-Finnish (FIN) AF: 0.144 AC: 725 AN: 5020

Middle Eastern (MID) AF: 0.205 AC: 48 AN: 234

European-Non Finnish (NFE) AF: 0.283 AC: 16528 AN: 58490

Other (OTH) AF: 0.225 AC: 360 AN: 1598

Alfa AF: 0.0595 Hom.: 153

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.39
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74804400; hg19: chr10-114710208; COSMIC: COSV60503433; COSMIC: COSV60503433;