2-47046329-A-G

Position:

chr2-47046329-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_020458.4(TTC7A):c.1817A>G(p.Lys606Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00298 in 1,613,908 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0031 ( 10 hom. )

Consequence

TTC7A
NM_020458.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 6.76

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015966624).

BP6

Variant 2-47046329-A-G is Benign according to our data. Variant chr2-47046329-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242606.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}. Variant chr2-47046329-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00208 (317/152338) while in subpopulation NFE AF= 0.00343 (233/68026). AF 95% confidence interval is 0.00306. There are 1 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC7A	NM_020458.4 linkuse as main transcript	c.1817A>G	p.Lys606Arg	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.1817A>G	p.Lys606Arg	missense_variant	16/20	2	NM_020458.4	P1	Q9ULT0-1

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

317

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00342

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00213

AC:

536

AN:

251304

Hom.:

AF XY:

0.00211

AC XY:

287

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000550

Gnomad ASJ exome

AF:

0.00934

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00134

Gnomad NFE exome

AF:

0.00324

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00308

AC:

4499

AN:

1461570

Hom.:

Cov.:

AF XY:

0.00300

AC XY:

2180

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00953

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00114

Gnomad4 NFE exome

AF:

0.00350

Gnomad4 OTH exome

AF:

0.00422

GnomAD4 genome

AF:

0.00208

AC:

317

AN:

152338

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00343

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00338

Hom.:

Bravo

AF:

0.00198

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00206

AC:

250

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00376

EpiControl

AF:

0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2021	Has been observed in with the S672P variant in multiple cases; in cases where phase was determined, it has been observed in cis with S672P in one individual with combined immunodeficiency with multiple intestinal atresias who harbored an another TTC7A variant in trans (Chen et al., 2013), and has also been observed in trans with the S672P in another individual with common variable immunodeficiency (Lawless et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In addition, in silico splice predictors suggest this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 28930861, 30443250, 23830146, 28808844, 27418642, 31814065) -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 21, 2022	PM3_Supporting, BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 25, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	TTC7A: BS1 -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 13, 2020

Variant summary: TTC7A c.1817A>G (p.Lys606Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251304 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 6-fold the estimated maximal expected allele frequency for a pathogenic variant in TTC7A causing Severe Combined Immunodeficiency Syndrome phenotype (0.00035), suggesting that the variant is benign. c.1817A>G has been reported in the literature in cis with c.2014T>C, p.Ser672Pro in at least one individual affected with Combined Immunodeficiency with Multiple Intestinal Atresias (CID-MIA), who had a likely pathogenic variant (c.1000DelAAGT) in compound heterozygosity (e.g. Chen_2013). The variant has also been detected in several patients with early-onset inflammatory bowel disease (EOIBD) or inflammatory bowel disease (IBD), often occurring along with c.2014T>C, p.Ser672Pro (e.g. Kammermeier_2016, Petersen_2017, Ashton, 2020). In some cases, the variants were indicated to have been inherited as a complex allele, while in others, the phase was not reported. However, these two variants were also reported in trans in at least one individual affected by a mild form of Combined Variable Immunodeficiency Syndrome (CVID), suggesting that the variants could possibly be associated with a mild form of disease when found on separate alleles (e.g. Lawless_2017). The c.1817A>G and c.2014T>C variants were also reported in compound heterozygosity in an individual evaluated for IPEX (Immune Dysregulation, Polyendocrinopathy, Ebteropathy, X-Linked) Syndrome (e.g. Gambineri_2018). These findings do not provide unequivocal evidence for association of the variant with Severe Combined Immunodeficiency Syndrome. To the best of our knowledge, no experimental studies evaluating an impact on protein function have been reported. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as likely benign, and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Gastrointestinal defects and immunodeficiency syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Apr 11, 2023

Criteria applied: PS4_MOD, PS3_SUP, PP3 -

TTC7A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Multiple gastrointestinal atresias

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.46

.;T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.071

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.5

.;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.74

MVP

0.74

MPC

0.36

ClinPred

0.63

GERP RS

5.5

Varity_R

0.64

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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