10-112950449-GTTTT-GT

Variant names:

• chr10-112950449-GTTT-G
• rs74804400
• NM_001367943.1:c.-296_-294delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001367943.1(TCF7L2):​c.-296_-294delTTT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000538 in 74,388 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 17)
  • Exomes 𝑓: 0.00054 (0 hom.)
  • Failed GnomAD Quality Control
• 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: PanelApp Australia, G2P
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.-296_-294delTTT		5_prime_UTR	Exon 1 of 15	NP_001354872.1	Q9NQB0-1
	TCF7L2	NM_001146274.2		c.-296_-294delTTT		5_prime_UTR	Exon 1 of 14	NP_001139746.1	Q9NQB0-7
	TCF7L2	NM_030756.5		c.-296_-294delTTT		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.-296_-294delTTT		5_prime_UTR	Exon 1 of 15	ENSP00000348274.4	Q9NQB0-1
	TCF7L2	ENST00000627217.3	TSL:1	c.-296_-294delTTT		5_prime_UTR	Exon 1 of 14	ENSP00000486891.1	Q9NQB0-7
	TCF7L2	ENST00000369397.8	TSL:1	c.-296_-294delTTT		5_prime_UTR	Exon 1 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 120626 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000538 AC: 40 AN: 74388 Hom.: 0 AF XY: 0.000538 AC XY: 20 AN XY: 37154

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

African (AFR) AF: 0.000839 AC: 2 AN: 2384

American (AMR) AF: 0.000426 AC: 1 AN: 2350

Ashkenazi Jewish (ASJ) AF: 0.000291 AC: 1 AN: 3442

East Asian (EAS) AF: 0.000596 AC: 5 AN: 8390

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: 0.000608 AC: 27 AN: 44396

Other (OTH) AF: 0.000762 AC: 4 AN: 5250

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 120626 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 56894

African (AFR) AF: 0.00 AC: 0 AN: 32312

American (AMR) AF: 0.00 AC: 0 AN: 11430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3082

East Asian (EAS) AF: 0.00 AC: 0 AN: 4118

South Asian (SAS) AF: 0.00 AC: 0 AN: 3462

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 250

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 58554

Other (OTH) AF: 0.00 AC: 0 AN: 1594

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs74804400;

hg19: chr10-114710208;