rs144971707

Positions:

chr2-46994487-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_020458.4(TTC7A):c.974G>A(p.Arg325Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000159 in 1,613,902 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R325W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TTC7A
NM_020458.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 4.68

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.061537772).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000519 (79/152082) while in subpopulation AFR AF= 0.0015 (62/41388). AF 95% confidence interval is 0.0012. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC7A	NM_020458.4 linkuse as main transcript	c.974G>A	p.Arg325Gln	missense_variant	7/20	ENST00000319190.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC7A	ENST00000319190.11 linkuse as main transcript	c.974G>A	p.Arg325Gln	missense_variant	7/20	2	NM_020458.4	P1	Q9ULT0-1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.000132

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000247

AC:

AN:

251184

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000121

AC:

177

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00191

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000441

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000519

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00150

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.000956

Alfa

AF:

0.000167

Hom.:

Bravo

AF:

0.000631

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Gastrointestinal defects and immunodeficiency syndrome 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 28, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 15, 2023	The TTC7A c.974G>A (p.Arg325Gln) missense variant has been reported in a homozygous state in two individuals with features of gastrointestinal defects and immunodeficiency syndrome in the medical literature (PMID: 31787977; 32531373). The highest frequency of this allele in the Genome Aggregation Database is 0.001498 in the African/African American population (version 3.1.2). Functional studies conducted in patient cells demonstrate that this variant results in reduced protein expression and function (PMID: 31787977). The c.974G>A variant was detected in trans with a variant of uncertain significance in this proband. Based on the available evidence, the c.974G>A (p.Arg325Gln) variant is classified as a variant of uncertain significance for gastrointestinal defects and immunodeficiency syndrome. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 12, 2022

Variant summary: TTC7A c.974G>A (p.Arg325Gln) results in a conservative amino acid change located in the Tetratricopeptide repeat protein 7, N-terminal domain (IPR045819) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251184 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TTC7A causing Severe Combined Immunodeficiency (0.00025 vs 0.00035), allowing no conclusion about variant significance. However, the frequency in the African subpopulation (0.0018) is much higher than estimated from disease prevalence. c.974G>A has been reported in the literature as a homozygous genotype in at-least two affected individuals with features of Primary Immunodeficiency who underwent a comprehensive NGS panel based diagnostic workup (example, Fusaro_2021, El-Daher_2019). At-least one of these two individuals reported a North African ethnicity (Fusaro_2021). One of these patients presented with recurrent lymphoproliferative syndrome and pan-hypergammaglobulinemia associated with chronic intestinal pseudo obstruction (CIPO) (El-Daher_2019). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (El-Daher_2019). The authors reported the mutant protein was unstable in B and T lymphoblasts leading to partial degradation, unable to stabilize subunits like EFR3 leading to low levels of EFR3 in B-cells and affected the ability of the mutant protein to regulate DNA accessibility, DNA stability and chromatin condensation. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Sep 21, 2022

PS3, PM3, BS1 -

Multiple gastrointestinal atresias

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

.;T;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.062

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

.;M;M

MutationTaster

Benign

0.89

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.087

Sift

Benign

0.24

T;T;T

Sift4G

Uncertain

0.045

D;D;D

Polyphen

0.88

P;D;.

Vest4

0.67

MVP

0.38

MPC

0.17

ClinPred

0.026

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.33

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