chr2-46956927-G-T

Position:

chr2-46956927-G-T

Variant summary

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

The NM_020458.4(TTC7A):c.437G>T(p.Arg146Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00636 in 1,614,206 control chromosomes in the GnomAD database, including 58 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 0.0046 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 53 hom. )

Consequence

TTC7A
NM_020458.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 3.62

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:

(HGNC:):

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=0.008859396).

BP6

Variant 2-46956927-G-T is Benign according to our data. Variant chr2-46956927-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458800.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00465 (708/152316) while in subpopulation NFE AF= 0.00701 (477/68030). AF 95% confidence interval is 0.00649. There are 5 homozygotes in gnomad4. There are 357 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC7A	NM_020458.4 linkuse as main transcript	c.437G>T	p.Arg146Leu	missense_variant	3/20	ENST00000319190.11	NP_065191.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC7A	ENST00000319190.11 linkuse as main transcript	c.437G>T	p.Arg146Leu	missense_variant	3/20	2	NM_020458.4	ENSP00000316699	P1	Q9ULT0-1
	ENST00000607950.1 linkuse as main transcript			upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.00465

AC:

707

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.00386

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00700

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00484

AC:

1217

AN:

251492

Hom.:

AF XY:

0.00504

AC XY:

685

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00114

Gnomad FIN exome

AF:

0.00337

Gnomad NFE exome

AF:

0.00884

Gnomad OTH exome

AF:

0.00440

GnomAD4 exome

AF:

0.00654

AC:

9555

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00643

AC XY:

4676

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.00145

Gnomad4 ASJ exome

AF:

0.000497

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00177

Gnomad4 FIN exome

AF:

0.00365

Gnomad4 NFE exome

AF:

0.00793

Gnomad4 OTH exome

AF:

0.00449

GnomAD4 genome

AF:

0.00465

AC:

708

AN:

152316

Hom.:

Cov.:

AF XY:

0.00479

AC XY:

357

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00386

Gnomad4 NFE

AF:

0.00701

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00152

Hom.:

Bravo

AF:

0.00425

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00721

AC:

ExAC

AF:

0.00572

AC:

694

EpiCase

AF:

0.00654

EpiControl

AF:

0.00569

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Multiple gastrointestinal atresias

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Gastrointestinal defects and immunodeficiency syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jun 14, 2021

TTC7A NM_020458.2 exon 3 p.Arg146Leu (c.437G>T): This variant has not been reported in the literature but is present in 0.6% (476/68038) of European alleles including 4 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-46956927-G-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:458800). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.437G>T (p.R146L) alteration is located in exon 3 (coding exon 3) of the TTC7A gene. This alteration results from a G to T substitution at nucleotide position 437, causing the arginine (R) at amino acid position 146 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

TTC7A: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.42

.;T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

0.000018

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.85

D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.0089

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Benign

0.20

Sift

Benign

0.14

T;T;D

Sift4G

Benign

0.088

T;T;T

Polyphen

0.0050

B;B;.

Vest4

0.48

MVP

0.31

MPC

0.092

ClinPred

0.025

GERP RS

4.9

Varity_R

0.27

gMVP

0.49

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