rs114276698

chr2-47011391-G-Achr2-47011391-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020458.4(TTC7A):c.1348G>A(p.Val450Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,611,706 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: TTC7A NM_020458.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.876

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018479526).
• BP6: Variant 2-47011391-G-A is Benign according to our data. Variant chr2-47011391-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 528467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47011391-G-A is described in Lovd as [Likely_benign]. Variant chr2-47011391-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00133 (203/152266) while in subpopulation NFE AF= 0.00226 (154/68016). AF 95% confidence interval is 0.00197. There are 0 homozygotes in gnomad4. There are 94 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC7A	NM_020458.4	c.1348G>A	p.Val450Met	missense_variant	11/20	ENST00000319190.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC7A	ENST00000319190.11	c.1348G>A	p.Val450Met	missense_variant	11/20	2	NM_020458.4	P1

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00228

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00157 AC: 392 AN: 249268 Hom.: 2 AF XY: 0.00154 AC XY: 208 AN XY: 134890

Gnomad AFR exome AF: 0.000617

Gnomad AMR exome AF: 0.000814

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000753

Gnomad FIN exome AF: 0.000149

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00200 AC: 2913 AN: 1459440 Hom.: 2 Cov.: 30 AF XY: 0.00194 AC XY: 1409 AN XY: 726118

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000761

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.000585

Gnomad4 NFE exome AF: 0.00232

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74472

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00226

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00210 Hom.: 3

Bravo AF: 0.00138

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00166 AC: 202

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00208

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 22, 2021	This variant is associated with the following publications: (PMID: 28930861) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -

TTC7A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	0.97	N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.049	D;D;D
Sift4G	Uncertain	0.031	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.71
MVP		0.41
MPC		0.31
ClinPred		0.010	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.039
gMVP		0.30

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

Other links and lift over

dbSNP: rs114276698; hg19: chr2-47238530;