rs587776971

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000319190.11(TTC7A):​c.1000_1001+2delAAGT​(p.Asn334SerfsTer28) variant causes a frameshift, splice donor, splice region, intron change. The variant allele was found at a frequency of 0.0000266 in 1,613,646 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

TTC7A
ENST00000319190.11 frameshift, splice_donor, splice_region, intron

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.50
Variant links:
Genes affected
TTC7A (HGNC:19750): (tetratricopeptide repeat domain 7A) This gene encodes a protein containing tetratricopeptide repeats. Mutations in this gene disrupt intestinal development and can cause early onset inflammatory bowel disease and intestinal atresia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-46994512-CAAGT-C is Pathogenic according to our data. Variant chr2-46994512-CAAGT-C is described in ClinVar as [Pathogenic]. Clinvar id is 50608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-46994512-CAAGT-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTC7ANM_020458.4 linkc.1001+3_1001+6delAAGT splice_region_variant, intron_variant Intron 7 of 19 ENST00000319190.11 NP_065191.2 Q9ULT0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTC7AENST00000319190.11 linkc.1000_1001+2delAAGT p.Asn334SerfsTer28 frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant Exon 7 of 20 2 NM_020458.4 ENSP00000316699.5 Q9ULT0-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152134
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000588
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000359
AC:
9
AN:
250650
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135568
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000795
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
38
AN:
1461512
Hom.:
0
AF XY:
0.0000275
AC XY:
20
AN XY:
727042
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000333
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152134
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Gastrointestinal defects and immunodeficiency syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMar 26, 2024- -
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 01, 2013- -
Pathogenic, criteria provided, single submitterresearchAleixo Muise Laboratory, Hospital For Sick ChildrenJul 05, 2024PS1;PM2;PM3;PP3;PP4 -
TTC7A-related disorder Pathogenic:1
Pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 04, 2024The TTC7A c.1001+3_1001+6delAAGT variant is predicted to result in an intronic deletion. This variant was reported in the homozygous and compound heterozygous state with a second pathogenic variant in multiple individuals with multiple intestinal atresia (also described as c.53344_53347delAAGT or c.1000delAAGT; Samuels et al. 2013. PubMed ID: 23423984; Chen et al. 2013. PubMed ID: 23830146; Table E1, Stray-Pedersen et al. 2016. PubMed ID: 27577878; Mandiá et al. 2018. PubMed ID: 29879038). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_DL_spliceai
1.0
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587776971; hg19: chr2-47221651; API