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Variant names:

Variant summary

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

The NM_001083962.2(TCF4):c.72+835_73-802dupGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene TCF4 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00015 ( 1 hom., cov: 0)

Exomes 𝑓: 0.00044 ( 49 hom. )

Failed GnomAD Quality Control

Consequence

TCF4
NM_001083962.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Publications

0 publications found

Variant links:

Genes affected

TCF4 (HGNC:11634): (transcription factor 4) This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]

TCF4 Gene-Disease associations (from GenCC):

Pitt-Hopkins syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
corneal dystrophy, Fuchs endothelial, 3
Inheritance: AD Classification: STRONG Submitted by: G2P
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fuchs' endothelial dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autism spectrum disorder
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

TCF4 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001083962.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for TCF4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000148 (20/135540) while in subpopulation SAS AF = 0.000502 (2/3988). AF 95% confidence interval is 0.000124. There are 1 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 20 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083962.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TCF4	NM_001083962.2	MANE Select	c.72+835_73-802dupGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT	intron	N/A	NP_001077431.1	P15884-3
TCF4	NM_001243226.3		c.378+835_379-802dupGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT	intron	N/A	NP_001230155.2	E9PH57
TCF4	NM_001243228.2		c.72+835_73-802dupGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT	intron	N/A	NP_001230157.1	H3BTP3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TCF4	ENST00000354452.8	TSL:5 MANE Select	c.72+835_73-802dupGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT	intron	N/A	ENSP00000346440.3	P15884-3
TCF4	ENST00000398339.5	TSL:1	c.378+835_379-802dupGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT	intron	N/A	ENSP00000381382.1	E9PH57
TCF4	ENST00000356073.8	TSL:1	c.72+835_73-802dupGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCT	intron	N/A	ENSP00000348374.4	P15884-1

Frequencies

GnomAD3 genomes

AF:

0.000148

AC:

AN:

135448

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000240

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000232

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000501

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000979

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000437

AC:

250

AN:

572534

Hom.:

Cov.:

AF XY:

0.000415

AC XY:

124

AN XY:

299116

show subpopulations

African (AFR)

AF:

0.000222

AC:

AN:

18026

American (AMR)

AF:

0.000318

AC:

AN:

22000

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

14912

East Asian (EAS)

AF:

0.000830

AC:

AN:

24082

South Asian (SAS)

AF:

0.000451

AC:

AN:

53210

European-Finnish (FIN)

AF:

0.000385

AC:

AN:

23366

Middle Eastern (MID)

AF:

0.00123

AC:

AN:

2436

European-Non Finnish (NFE)

AF:

0.000403

AC:

156

AN:

386738

Other (OTH)

AF:

0.000684

AC:

AN:

27764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.580

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000148

AC:

AN:

135540

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

65550

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

37660

American (AMR)

AF:

0.000232

AC:

AN:

12942

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3176

East Asian (EAS)

AF:

0.00

AC:

AN:

4382

South Asian (SAS)

AF:

0.000502

AC:

AN:

3988

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9126

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.0000979

AC:

AN:

61270

Other (OTH)

AF:

0.00

AC:

AN:

1876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.581

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

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.

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