Genetic Variant TCF7L2:p.Met1fs (chr10-112950748-G-GA) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 4P and 9B. PVS1_StrongBP6BS1BS2

The NM_001367943.1(TCF7L2):c.1dupA(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 0.00253 in 1,533,132 control chromosomes in the GnomAD database, including 61 homozygotes. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.010 ( 24 hom., cov: 29)

Exomes 𝑓: 0.0017 ( 37 hom. )

Consequence

TCF7L2
NM_001367943.1 frameshift, start_lost

Scores

Not classified

Clinical Significance

Benign no assertion criteria provided B:1O:1

Conservation

PhyloP100: 1.35

Publications

0 publications found

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]

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

TCF7L2 links:

ENSG00000233547 (HGNC:):

ENSG00000233547 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 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. There are 8 pathogenic variants in the truncated region.

BP6

Variant 10-112950748-G-GA is Benign according to our data. Variant chr10-112950748-G-GA is described in ClinVar as Benign. ClinVar VariationId is 3257944.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1529/149880) while in subpopulation AFR AF = 0.0337 (1375/40810). AF 95% confidence interval is 0.0322. There are 24 homozygotes in GnomAd4. There are 728 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAd4 at 1529 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCF7L2	NM_001367943.1	MANE Select	c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 15	NP_001354872.1	Q9NQB0-1
TCF7L2	NM_001146274.2		c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 14	NP_001139746.1	Q9NQB0-7
TCF7L2	NM_030756.5		c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 14	NP_110383.2	Q9NQB0-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCF7L2	ENST00000355995.9	TSL:1 MANE Select	c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 15	ENSP00000348274.4	Q9NQB0-1
TCF7L2	ENST00000627217.3	TSL:1	c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 14	ENSP00000486891.1	Q9NQB0-7
TCF7L2	ENST00000369397.8	TSL:1	c.1dupA	p.Met1fs	frameshift start_lost	Exon 1 of 14	ENSP00000358404.4	Q9NQB0-8

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1528

AN:

149780

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00565

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00741

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000134

Gnomad OTH

AF:

0.0102

GnomAD2 exomes

AF:

0.00364

AC:

447

AN:

122762

AF XY:

0.00296

show subpopulations

Gnomad AFR exome

AF:

0.0408

Gnomad AMR exome

AF:

0.00372

Gnomad ASJ exome

AF:

0.000777

Gnomad EAS exome

AF:

0.00400

Gnomad FIN exome

AF:

0.000137

Gnomad NFE exome

AF:

0.000783

Gnomad OTH exome

AF:

0.00209

GnomAD4 exome

AF:

0.00170

AC:

2348

AN:

1383252

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

1096

AN XY:

682506

show subpopulations

African (AFR)

AF:

0.0330

AC:

1030

AN:

31248

American (AMR)

AF:

0.00259

AC:

AN:

33176

Ashkenazi Jewish (ASJ)

AF:

0.000122

AC:

AN:

24612

East Asian (EAS)

AF:

0.0224

AC:

819

AN:

36608

South Asian (SAS)

AF:

0.000494

AC:

AN:

76952

European-Finnish (FIN)

AF:

0.0000203

AC:

AN:

49164

Middle Eastern (MID)

AF:

0.000241

AC:

AN:

4148

European-Non Finnish (NFE)

AF:

0.000216

AC:

231

AN:

1070304

Other (OTH)

AF:

0.00244

AC:

139

AN:

57040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

108

216

325

433

541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0102

AC:

1529

AN:

149880

Hom.:

Cov.:

AF XY:

0.00995

AC XY:

728

AN XY:

73134

show subpopulations

African (AFR)

AF:

0.0337

AC:

1375

AN:

40810

American (AMR)

AF:

0.00564

AC:

AN:

15064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00743

AC:

AN:

5114

South Asian (SAS)

AF:

0.000213

AC:

AN:

4704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000134

AC:

AN:

67396

Other (OTH)

AF:

0.0101

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

137

206

274

343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00114

Hom.:

Asia WGS

AF:

0.00491

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

TCF7L2-related disorder (1)

Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.4

Mutation Taster

=297/3

polymorphism

(source)

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

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10-112950748-GAA-GAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over