rs113997845

Positions:

• chr2-46994386-G-C
• chr2-46994386-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_020458.4(TTC7A):​c.873G>C​(p.Leu291=) 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:2
• Conservation: PhyloP100: 0.796

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC7A	NM_020458.4	c.873G>C	p.Leu291=	synonymous_variant	7/20	ENST00000319190.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC7A	ENST00000319190.11	c.873G>C	p.Leu291=	synonymous_variant	7/20	2	NM_020458.4	P1

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

GnomAD3 exomes AF: 0.00653 AC: 1635 AN: 250204 Hom.: 4 AF XY: 0.00670 AC XY: 907 AN XY: 135336

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 SAS exome AF: 0.00252

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

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00256

Gnomad4 FIN exome AF: 0.00478

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.00807

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

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00379

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

TTC7A: BP4, BP7, BS1, BS2 -

Multiple gastrointestinal atresias Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.0
DANN	Benign	0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs113997845; hg19: chr2-47221525;