rs61746139

Variant names:

• chr2-46956927-G-A
• rs61746139
• NM_020458.4:c.437G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-46956927-G-A
• chr2-46956927-G-C
• chr2-46956927-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020458.4(TTC7A):​c.437G>A​(p.Arg146Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00046 in 1,614,206 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R146L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (7 hom.)
• Consequence: TTC7A NM_020458.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.62
• 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: ClinGen, Orphanet, Ambry Genetics

ENSG00000272814 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00838691).
• BP6: Variant 2-46956927-G-A is Benign according to our data. Variant chr2-46956927-G-A is described in ClinVar as Benign. ClinVar VariationId is 712939.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000558 (85/152316) while in subpopulation EAS AF = 0.0135 (70/5178). AF 95% confidence interval is 0.011. There are 2 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.437G>A	p.Arg146Gln	missense	Exon 3 of 20	NP_065191.2	Q9ULT0-1
	TTC7A	NM_001288951.2		c.437G>A	p.Arg146Gln	missense	Exon 3 of 21	NP_001275880.1	Q9ULT0-4
	TTC7A	NM_001288953.2		c.335G>A	p.Arg112Gln	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.437G>A	p.Arg146Gln	missense	Exon 3 of 20	ENSP00000316699.5	Q9ULT0-1
	TTC7A	ENST00000394850.6	TSL:1	c.437G>A	p.Arg146Gln	missense	Exon 3 of 21	ENSP00000378320.2	Q9ULT0-4
	TTC7A	ENST00000409825.5	TSL:1	n.*128G>A		non_coding_transcript_exon	Exon 3 of 21	ENSP00000386521.1	H0Y3V7

Frequencies

GnomAD3 genomes AF: 0.000558 AC: 85 AN: 152198 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0135

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00113 AC: 285 AN: 251492 AF XY: 0.00105

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0137

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000449 AC: 657 AN: 1461890 Hom.: 7 Cov.: 31 AF XY: 0.000458 AC XY: 333 AN XY: 727248

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

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

East Asian (EAS) AF: 0.0119 AC: 473 AN: 39700

South Asian (SAS) AF: 0.000730 AC: 63 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1112012

Other (OTH) AF: 0.00137 AC: 83 AN: 60394

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152316 Hom.: 2 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74468

African (AFR) AF: 0.0000962 AC: 4 AN: 41578

American (AMR) AF: 0.000131 AC: 2 AN: 15300

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

East Asian (EAS) AF: 0.0135 AC: 70 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00531 Hom.: 6

Bravo AF: 0.000525

ExAC AF: 0.00114 AC: 138

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Multiple gastrointestinal atresias (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.093
Sift	Benign	0.24	T
Sift4G	Uncertain	0.029	D
Polyphen		0.050	B
Vest4		0.48
MVP		0.26
MPC		0.086
ClinPred		0.016	T
GERP RS		4.9
Varity_R		0.067
gMVP		0.33
Mutation Taster		=99/1	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: rs61746139; hg19: chr2-47184066;