rs114276698

Variant names:

• chr2-47011391-G-A
• rs114276698
• NM_020458.4:c.1348G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47011391-G-A
• chr2-47011391-G-C
• chr2-47011391-G-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.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. 13/22 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:8
• Conservation: PhyloP100: 0.876
• 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 528467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC7A	NM_020458.4	MANE Select	c.1348G>A	p.Val450Met	missense	Exon 11 of 20	NP_065191.2	Q9ULT0-1
	TTC7A	NM_001288951.2		c.1348G>A	p.Val450Met	missense	Exon 11 of 21	NP_001275880.1	Q9ULT0-4
	TTC7A	NM_001288953.2		c.1246G>A	p.Val416Met	missense	Exon 12 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.1348G>A	p.Val450Met	missense	Exon 11 of 20	ENSP00000316699.5	Q9ULT0-1
	TTC7A	ENST00000394850.6	TSL:1	c.1348G>A	p.Val450Met	missense	Exon 11 of 21	ENSP00000378320.2	Q9ULT0-4
	TTC7A	ENST00000409825.5	TSL:1	n.*1097G>A		non_coding_transcript_exon	Exon 12 of 21	ENSP00000386521.1	H0Y3V7

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

GnomAD2 exomes AF: 0.00157 AC: 392 AN: 249268 AF XY: 0.00154

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 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

African (AFR) AF: 0.000508 AC: 17 AN: 33478

American (AMR) AF: 0.000761 AC: 34 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86178

European-Finnish (FIN) AF: 0.000585 AC: 30 AN: 51290

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

European-Non Finnish (NFE) AF: 0.00232 AC: 2580 AN: 1111868

Other (OTH) AF: 0.00154 AC: 93 AN: 60356

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

African (AFR) AF: 0.000530 AC: 22 AN: 41548

American (AMR) AF: 0.000784 AC: 12 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00226 AC: 154 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00184 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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	1	Multiple gastrointestinal atresias (1)
-	-	1	TTC7A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.88
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.20
Sift	Benign	0.049	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	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
Mutation Taster		=96/4	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: rs114276698; hg19: chr2-47238530;