10-112950748-GAA-G

Variant names:

• chr10-112950748-GAA-G
• NM_001367943.1:c.-1_1delAA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001367943.1(TCF7L2):​c.-1_1delAA​(p.Met1fs) variant causes a frameshift, start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000289 in 1,384,198 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TCF7L2 NM_001367943.1 frameshift, start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.67

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]

ENSG00000233547 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.999 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCF7L2	NM_001367943.1	c.-1_1delAA	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 15	ENST00000355995.9	NP_001354872.1
TCF7L2	NM_001367943.1	c.-1_1delAA		5_prime_UTR_variant	Exon 1 of 15	ENST00000355995.9	NP_001354872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCF7L2	ENST00000355995.9	c.-1_1delAA	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 15	1	NM_001367943.1	ENSP00000348274.4
TCF7L2	ENST00000355995	c.-1_1delAA		5_prime_UTR_variant	Exon 1 of 15	1	NM_001367943.1	ENSP00000348274.4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1384198 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 682938

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000273

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000280

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-114710507;