dbSNP rs74804400: TCF7L2:c.-297_-294delTTTT (chr10-112950449-GTTTT-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

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

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.60

Publications

1 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: 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

Gene	Transcript	Tags	HGVSc	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

Gene	Transcript	Tags	HGVSc	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.:

Cov.:

show subpopulations

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:

AN:

74544

Hom.:

AF XY:

0.000215

AC XY:

AN XY:

37228

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

2394

American (AMR)

AF:

0.00934

AC:

AN:

2356

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3452

East Asian (EAS)

AF:

0.00

AC:

AN:

8426

South Asian (SAS)

AF:

0.00

AC:

AN:

6312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

362

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

44480

Other (OTH)

AF:

0.000190

AC:

AN:

5260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00172

AC:

207

AN:

120642

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

140

AN XY:

56922

show subpopulations

African (AFR)

AF:

0.0000309

AC:

AN:

32358

American (AMR)

AF:

0.0177

AC:

203

AN:

11440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3084

East Asian (EAS)

AF:

0.00

AC:

AN:

4106

South Asian (SAS)

AF:

0.00

AC:

AN:

3456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

58542

Other (OTH)

AF:

0.00125

AC:

AN:

1598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.562

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

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

Publications

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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