2-47046361-G-C

Position:

chr2-47046361-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_020458.4(TTC7A):c.1849G>C(p.Glu617Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TTC7A
NM_020458.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.24

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]

TTC7A links:

STPG4 (HGNC:26850): (sperm-tail PG-rich repeat containing 4) Predicted to enable chromatin binding activity and histone binding activity. Predicted to be involved in DNA demethylation of male pronucleus and positive regulation of DNA demethylation. Predicted to act upstream of or within C-5 methylation of cytosine. Predicted to be located in cytoplasm and nucleus. Predicted to be active in female pronucleus; germinal vesicle; and male pronucleus. [provided by Alliance of Genome Resources, Apr 2022]

STPG4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35102186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC7A	NM_020458.4 linkuse as main transcript	c.1849G>C	p.Glu617Gln	missense_variant	16/20	ENST00000319190.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC7A	ENST00000319190.11 linkuse as main transcript	c.1849G>C	p.Glu617Gln	missense_variant	16/20	2	NM_020458.4	P1	Q9ULT0-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251444

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.000185

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.000169

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Multiple gastrointestinal atresias

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 617 of the TTC7A protein (p.Glu617Gln). This variant is present in population databases (rs376138112, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with TTC7A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1502570). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

.;T;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.35

T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.1

.;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.18

Sift

Uncertain

0.029

D;D;D

Sift4G

Benign

0.073

T;T;T

Polyphen

0.93

P;D;.

Vest4

0.41

MVP

0.77

MPC

0.19

ClinPred

0.85

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.19

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over