rs373426839

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.67
Variant links:
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]

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ACMG classification

Classification made for transcript

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
TCF7L2NM_001367943.1 linkc.-1_1delAA p.Met1fs frameshift_variant, start_lost Exon 1 of 15 ENST00000355995.9 NP_001354872.1
TCF7L2NM_001367943.1 linkc.-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
TCF7L2ENST00000355995.9 linkc.-1_1delAA p.Met1fs frameshift_variant, start_lost Exon 1 of 15 1 NM_001367943.1 ENSP00000348274.4 Q9NQB0-1
TCF7L2ENST00000355995 linkc.-1_1delAA 5_prime_UTR_variant Exon 1 of 15 1 NM_001367943.1 ENSP00000348274.4 Q9NQB0-1

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
show subpopulations
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

Name
Calibrated prediction
Score
Prediction

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; API