NM_020458.4:c.433G>A

Variant names:

• chr2-46956923-G-A
• rs201163893
• NM_020458.4:c.433G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_020458.4(TTC7A):​c.433G>A​(p.Ala145Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,614,076 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A145S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: TTC7A NM_020458.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.25
• Publications: 5 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

ENSG00000272814 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35171968).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC7A	NM_020458.4	MANE Select	c.433G>A	p.Ala145Thr	missense	Exon 3 of 20	NP_065191.2	Q9ULT0-1
	TTC7A	NM_001288951.2		c.433G>A	p.Ala145Thr	missense	Exon 3 of 21	NP_001275880.1	Q9ULT0-4
	TTC7A	NM_001288953.2		c.331G>A	p.Ala111Thr	missense	Exon 4 of 21	NP_001275882.1	G5E9G4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC7A	ENST00000319190.11	TSL:2 MANE Select	c.433G>A	p.Ala145Thr	missense	Exon 3 of 20	ENSP00000316699.5	Q9ULT0-1
	TTC7A	ENST00000394850.6	TSL:1	c.433G>A	p.Ala145Thr	missense	Exon 3 of 21	ENSP00000378320.2	Q9ULT0-4
	TTC7A	ENST00000409825.5	TSL:1	n.*124G>A		non_coding_transcript_exon	Exon 3 of 21	ENSP00000386521.1	H0Y3V7

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 251490 AF XY: 0.000169

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000316

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000170 AC: 248 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.000172 AC XY: 125 AN XY: 727246

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000209 AC: 232 AN: 1112008

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74342

African (AFR) AF: 0.0000724 AC: 3 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.000132

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Multiple gastrointestinal atresias (1)
-	1	-	TTC7A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
PhyloP100		9.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.18
Sift	Benign	0.24	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.26	B
Vest4		0.60
MVP		0.33
MPC		0.20
ClinPred		0.11	T
GERP RS		5.8
Varity_R		0.11
gMVP		0.21
Mutation Taster		=191/109	polymorphism

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: rs201163893; hg19: chr2-47184062;