chr2-47005985-C-G

Variant names:

• chr2-47005985-C-G
• rs117304542
• NM_020458.4:c.1129C>G

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.1129C>G​(p.Gln377Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00384 in 1,613,960 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (165 hom.)
• Consequence: TTC7A NM_020458.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.08
• 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=0.0039553344).
• BP6: Variant 2-47005985-C-G is Benign according to our data. Variant chr2-47005985-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445493.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 = 0.00296 (450/152086) while in subpopulation SAS AF = 0.0461 (222/4812). AF 95% confidence interval is 0.0412. There are 9 homozygotes in GnomAd4. There are 260 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.1129C>G	p.Gln377Glu	missense	Exon 9 of 20	NP_065191.2
	TTC7A	NM_001288951.2		c.1129C>G	p.Gln377Glu	missense	Exon 9 of 21	NP_001275880.1
	TTC7A	NM_001288953.2		c.1027C>G	p.Gln343Glu	missense	Exon 10 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.1129C>G	p.Gln377Glu	missense	Exon 9 of 20	ENSP00000316699.5
	TTC7A	ENST00000394850.6	TSL:1	c.1129C>G	p.Gln377Glu	missense	Exon 9 of 21	ENSP00000378320.2
	TTC7A	ENST00000409825.5	TSL:1	n.*878C>G		non_coding_transcript_exon	Exon 10 of 21	ENSP00000386521.1

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 151968 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0330

Gnomad SAS AF: 0.0465

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00787 AC: 1978 AN: 251408 AF XY: 0.00943

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.0328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00393 AC: 5747 AN: 1461874 Hom.: 165 Cov.: 31 AF XY: 0.00508 AC XY: 3697 AN XY: 727232

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26136

East Asian (EAS) AF: 0.0417 AC: 1655 AN: 39700

South Asian (SAS) AF: 0.0412 AC: 3553 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000189 AC: 210 AN: 1112012

Other (OTH) AF: 0.00479 AC: 289 AN: 60396

GnomAD4 genome AF: 0.00296 AC: 450 AN: 152086 Hom.: 9 Cov.: 32 AF XY: 0.00350 AC XY: 260 AN XY: 74306

African (AFR) AF: 0.000241 AC: 10 AN: 41512

American (AMR) AF: 0.00210 AC: 32 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0329 AC: 170 AN: 5164

South Asian (SAS) AF: 0.0461 AC: 222 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10544

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68000

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.000600 Hom.: 0

Bravo AF: 0.00179

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00847 AC: 1028

Asia WGS AF: 0.0260 AC: 92 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

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

not specified Benign:1

Dec 10, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	Benign	0.095
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.041
Sift	Benign	0.31	T
Sift4G	Uncertain	0.016	D
Polyphen		0.010	B
Vest4		0.46
MVP		0.34
MPC		0.090
ClinPred		0.016	T
GERP RS		4.0
Varity_R		0.066
gMVP		0.24
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117304542; hg19: chr2-47233124;