rs58422168

Positions:

• chr2-47073806-C-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.2460C>T​(p.Gly820=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,613,614 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (19 hom.)
• Consequence: TTC7A NM_020458.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.85

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]

STPG4 (HGNC:26850): (sperm-tail PG-rich repeat containing 4) Predicted to enable chromatin binding activity and histone binding activity. Predicted to be involved in DNA demethylation of male pronucleus and positive regulation of DNA demethylation. Predicted to act upstream of or within C-5 methylation of cytosine. Predicted to be located in cytoplasm and nucleus. Predicted to be active in female pronucleus; germinal vesicle; and male pronucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-47073806-C-T is Benign according to our data. Variant chr2-47073806-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 458797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47073806-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.85 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00255 (389/152266) while in subpopulation NFE AF= 0.00431 (293/68022). AF 95% confidence interval is 0.0039. There are 0 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTC7A	NM_020458.4	c.2460C>T	p.Gly820=	synonymous_variant	20/20	ENST00000319190.11	NP_065191.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC7A	ENST00000319190.11	c.2460C>T	p.Gly820=	synonymous_variant	20/20	2	NM_020458.4	ENSP00000316699	P1

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 389 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00227 AC: 568 AN: 250590 Hom.: 5 AF XY: 0.00217 AC XY: 294 AN XY: 135652

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00421

Gnomad NFE exome AF: 0.00397

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00348 AC: 5086 AN: 1461348 Hom.: 19 Cov.: 31 AF XY: 0.00338 AC XY: 2456 AN XY: 727008

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00409

Gnomad4 NFE exome AF: 0.00424

Gnomad4 OTH exome AF: 0.00190

GnomAD4 genome AF: 0.00255 AC: 389 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.00247 AC XY: 184 AN XY: 74452

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00405

Gnomad4 NFE AF: 0.00431

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00317 Hom.: 0

Bravo AF: 0.00193

EpiCase AF: 0.00284

EpiControl AF: 0.00362

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	TTC7A: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

TTC7A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Multiple gastrointestinal atresias Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.5
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs58422168; hg19: chr2-47300945; COSMIC: COSV55412938; COSMIC: COSV55412938;