chr10-112950449-GTTTT-G

Variant names:

• chr10-112950449-GTTTT-G
• rs74804400
• NM_001367943.1:c.-297_-294delTTTT

Variant summary

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

The NM_001367943.1(TCF7L2):​c.-297_-294delTTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 195,186 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 17)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: TCF7L2 NM_001367943.1 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• 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 amr. GnomAd4 allele frequency = 0.00172 (207/120642) while in subpopulation AMR AF = 0.0177 (203/11440). AF 95% confidence interval is 0.0157. There are 2 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 17. This position passed quality control check.
• BS2: High AC in GnomAd4 at 207 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.-297_-294delTTTT		5_prime_UTR	Exon 1 of 15	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.-297_-294delTTTT		5_prime_UTR	Exon 1 of 14	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.-297_-294delTTTT		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.-297_-294delTTTT		5_prime_UTR	Exon 1 of 15	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.-297_-294delTTTT		5_prime_UTR	Exon 1 of 14	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.-297_-294delTTTT		5_prime_UTR	Exon 1 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 207 AN: 120632 Hom.: 2 Cov.: 17

Gnomad AFR AF: 0.0000309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000171

Gnomad OTH AF: 0.00125

GnomAD4 exome AF: 0.000322 AC: 24 AN: 74544 Hom.: 0 AF XY: 0.000215 AC XY: 8 AN XY: 37228

African (AFR) AF: 0.000418 AC: 1 AN: 2394

American (AMR) AF: 0.00934 AC: 22 AN: 2356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 8426

South Asian (SAS) AF: 0.00 AC: 0 AN: 6312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 362

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 44480

Other (OTH) AF: 0.000190 AC: 1 AN: 5260

GnomAD4 genome AF: 0.00172 AC: 207 AN: 120642 Hom.: 2 Cov.: 17 AF XY: 0.00246 AC XY: 140 AN XY: 56922

African (AFR) AF: 0.0000309 AC: 1 AN: 32358

American (AMR) AF: 0.0177 AC: 203 AN: 11440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3084

East Asian (EAS) AF: 0.00 AC: 0 AN: 4106

South Asian (SAS) AF: 0.00 AC: 0 AN: 3456

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.0000171 AC: 1 AN: 58542

Other (OTH) AF: 0.00125 AC: 2 AN: 1598

Alfa AF: 0.00 Hom.: 153

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

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;