chr10-112950449-GT-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001367943.1(TCF7L2):​c.-294delT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.013 (25 hom., cov: 17)
  • Exomes 𝑓: 0.11 (1 hom.)
• Consequence: TCF7L2 NM_001367943.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0132 (1593/120580) while in subpopulation AFR AF = 0.0383 (1240/32348). AF 95% confidence interval is 0.0366. There are 25 homozygotes in GnomAd4. There are 725 alleles in the male GnomAd4 subpopulation. Median coverage is 17. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1593 AD,Unknown gene.

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.-294delT		5_prime_UTR	Exon 1 of 15	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.-294delT		5_prime_UTR	Exon 1 of 14	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.-294delT		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.-294delT		5_prime_UTR	Exon 1 of 15	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.-294delT		5_prime_UTR	Exon 1 of 14	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.-294delT		5_prime_UTR	Exon 1 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 1594 AN: 120570 Hom.: 25 Cov.: 17

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00454

Gnomad EAS AF: 0.00170

Gnomad SAS AF: 0.00260

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00400

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.0151

GnomAD4 exome AF: 0.109 AC: 7542 AN: 69076 Hom.: 1 Cov.: 0 AF XY: 0.103 AC XY: 3558 AN XY: 34614

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

African (AFR) AF: 0.190 AC: 419 AN: 2202

American (AMR) AF: 0.107 AC: 242 AN: 2264

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 413 AN: 3122

East Asian (EAS) AF: 0.173 AC: 1173 AN: 6762

South Asian (SAS) AF: 0.0541 AC: 336 AN: 6210

European-Finnish (FIN) AF: 0.0365 AC: 54 AN: 1480

Middle Eastern (MID) AF: 0.117 AC: 39 AN: 332

European-Non Finnish (NFE) AF: 0.102 AC: 4269 AN: 41870

Other (OTH) AF: 0.123 AC: 597 AN: 4834

⚠️ 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: 0.0132 AC: 1593 AN: 120580 Hom.: 25 Cov.: 17 AF XY: 0.0127 AC XY: 725 AN XY: 56884

African (AFR) AF: 0.0383 AC: 1240 AN: 32348

American (AMR) AF: 0.00560 AC: 64 AN: 11434

Ashkenazi Jewish (ASJ) AF: 0.00454 AC: 14 AN: 3084

East Asian (EAS) AF: 0.00170 AC: 7 AN: 4106

South Asian (SAS) AF: 0.00261 AC: 9 AN: 3454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5020

Middle Eastern (MID) AF: 0.00427 AC: 1 AN: 234

European-Non Finnish (NFE) AF: 0.00400 AC: 234 AN: 58500

Other (OTH) AF: 0.0150 AC: 24 AN: 1596

Alfa AF: 0.00 Hom.: 153

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

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: COSV60501548; COSMIC: COSV60501548;