2-46975047-A-C

Position:

• chr2-46975047-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020458.4(TTC7A):​c.592A>C​(p.Thr198Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T198A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTC7A NM_020458.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.304

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21011946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC7A	NM_020458.4	c.592A>C	p.Thr198Pro	missense_variant	4/20	ENST00000319190.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC7A	ENST00000319190.11	c.592A>C	p.Thr198Pro	missense_variant	4/20	2	NM_020458.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple gastrointestinal atresias Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 09, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with TTC7A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with proline at codon 198 of the TTC7A protein (p.Thr198Pro). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Uncertain	0.49	.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.047	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	.;L;L
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	D;D;D
REVEL	Benign	0.18
Sift	Benign	0.037	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.66	P;P;.
Vest4		0.35
MutPred		0.42		.;Gain of catalytic residue at T198 (P = 0.0014);Gain of catalytic residue at T198 (P = 0.0014);
MVP		0.099
MPC		0.13
ClinPred		0.56	D
GERP RS		-11
Varity_R		0.35
gMVP		0.50

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-47202186;