rs786205698

chr2-47024294-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_020458.4(TTC7A):c.1576C>T(p.Gln526Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TTC7A NM_020458.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.614

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 2-47024294-C-T is Pathogenic according to our data. Variant chr2-47024294-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 190393.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC7A	NM_020458.4	c.1576C>T	p.Gln526Ter	stop_gained	14/20	ENST00000319190.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC7A	ENST00000319190.11	c.1576C>T	p.Gln526Ter	stop_gained	14/20	2	NM_020458.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000411 AC: 1 AN: 243490 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 131690

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000301

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454086 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722818

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple gastrointestinal atresias Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 24, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 190393). This premature translational stop signal has been observed in individual(s) with very early onset inflammatory bowel disease (PMID: 24417819). This variant is present in population databases (rs786205698, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gln526*) in the TTC7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TTC7A are known to be pathogenic (PMID: 23830146, 24292712). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	44
Dann	Uncertain	0.99
Eigen	Uncertain	0.22
Eigen_PC	Benign	-0.052
FATHMM_MKL	Benign	0.091	N
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.29
GERP RS		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs786205698; hg19: chr2-47251433;