NM_020458.4:c.563G>T

Variant names:

• chr2-46975018-G-T
• rs147471840
• NM_020458.4:c.563G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020458.4(TTC7A):​c.563G>T​(p.Arg188Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00138 in 1,614,032 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R188H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (38 hom.)
• Consequence: TTC7A NM_020458.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.52
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• gastrointestinal defects and immunodeficiency syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• multiple intestinal atresia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065300465).
• BP6: Variant 2-46975018-G-T is Benign according to our data. Variant chr2-46975018-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000768 (117/152302) while in subpopulation SAS AF = 0.023 (111/4828). AF 95% confidence interval is 0.0195. There are 0 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 38 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020458.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC7A	NM_020458.4	MANE Select	c.563G>T	p.Arg188Leu	missense	Exon 4 of 20	NP_065191.2
	TTC7A	NM_001288951.2		c.563G>T	p.Arg188Leu	missense	Exon 4 of 21	NP_001275880.1
	TTC7A	NM_001288953.2		c.461G>T	p.Arg154Leu	missense	Exon 5 of 21	NP_001275882.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC7A	ENST00000319190.11	TSL:2 MANE Select	c.563G>T	p.Arg188Leu	missense	Exon 4 of 20	ENSP00000316699.5
	TTC7A	ENST00000394850.6	TSL:1	c.563G>T	p.Arg188Leu	missense	Exon 4 of 21	ENSP00000378320.2
	TTC7A	ENST00000409825.5	TSL:1	n.*312G>T		non_coding_transcript_exon	Exon 5 of 21	ENSP00000386521.1

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 117 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00294 AC: 740 AN: 251468 AF XY: 0.00397

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00145 AC: 2116 AN: 1461730 Hom.: 38 Cov.: 31 AF XY: 0.00210 AC XY: 1525 AN XY: 727166

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.0000894 AC: 4 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26134

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39694

South Asian (SAS) AF: 0.0224 AC: 1932 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1111908

Other (OTH) AF: 0.00147 AC: 89 AN: 60380

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74482

African (AFR) AF: 0.0000241 AC: 1 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0230 AC: 111 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000386 Hom.: 1

Bravo AF: 0.000340

ExAC AF: 0.00333 AC: 404

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 30, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TTC7A: BP4, BS1, BS2

Multiple gastrointestinal atresias Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.17
Sift	Benign	0.40	T
Sift4G	Benign	0.31	T
Polyphen		0.31	B
Vest4		0.74
MVP		0.45
MPC		0.12
ClinPred		0.043	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.32
gMVP		0.43
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs147471840; hg19: chr2-47202157;