2-46994386-G-C

Variant names:

• chr2-46994386-G-C
• rs113997845
• NM_020458.4:c.873G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020458.4(TTC7A):​c.873G>C​(p.Leu291Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00977 in 1,613,746 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L291L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (5 hom., cov: 32)
  • Exomes 𝑓: 0.010 (90 hom.)
• Consequence: TTC7A NM_020458.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.796
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 2-46994386-G-C is Benign according to our data. Variant chr2-46994386-G-C is described in ClinVar as Benign. ClinVar VariationId is 458804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.796 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00693 (1056/152280) while in subpopulation NFE AF = 0.0124 (845/68012). AF 95% confidence interval is 0.0117. There are 5 homozygotes in GnomAd4. There are 457 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.873G>C	p.Leu291Leu	synonymous	Exon 7 of 20	NP_065191.2	Q9ULT0-1
	TTC7A	NM_001288951.2		c.873G>C	p.Leu291Leu	synonymous	Exon 7 of 21	NP_001275880.1	Q9ULT0-4
	TTC7A	NM_001288953.2		c.771G>C	p.Leu257Leu	synonymous	Exon 8 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.873G>C	p.Leu291Leu	synonymous	Exon 7 of 20	ENSP00000316699.5	Q9ULT0-1
	TTC7A	ENST00000394850.6	TSL:1	c.873G>C	p.Leu291Leu	synonymous	Exon 7 of 21	ENSP00000378320.2	Q9ULT0-4
	TTC7A	ENST00000409825.5	TSL:1	n.*622G>C		non_coding_transcript_exon	Exon 8 of 21	ENSP00000386521.1	H0Y3V7

Frequencies

GnomAD3 genomes AF: 0.00694 AC: 1056 AN: 152162 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00570

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00653 AC: 1635 AN: 250204 AF XY: 0.00670

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00244

Gnomad ASJ exome AF: 0.00190

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00435

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00839

GnomAD4 exome AF: 0.0101 AC: 14717 AN: 1461466 Hom.: 90 Cov.: 31 AF XY: 0.00980 AC XY: 7123 AN XY: 727012

African (AFR) AF: 0.00134 AC: 45 AN: 33474

American (AMR) AF: 0.00304 AC: 136 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00256 AC: 221 AN: 86222

European-Finnish (FIN) AF: 0.00478 AC: 255 AN: 53376

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5756

European-Non Finnish (NFE) AF: 0.0122 AC: 13523 AN: 1111788

Other (OTH) AF: 0.00807 AC: 487 AN: 60376

GnomAD4 genome AF: 0.00693 AC: 1056 AN: 152280 Hom.: 5 Cov.: 32 AF XY: 0.00614 AC XY: 457 AN XY: 74454

African (AFR) AF: 0.00200 AC: 83 AN: 41556

American (AMR) AF: 0.00575 AC: 88 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4832

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0124 AC: 845 AN: 68012

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00991 Hom.: 0

Bravo AF: 0.00634

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.00986

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Multiple gastrointestinal atresias (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.0
DANN	Benign	0.81
PhyloP100		0.80
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: rs113997845; hg19: chr2-47221525;