rs2302416

Variant names:

• chr17-16003114-G-A
• rs2302416
• NM_017775.4:c.462+283G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017775.4(TTC19):​c.462+283G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0876 in 152,190 control chromosomes in the GnomAD database, including 1,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.088 (1581 hom., cov: 32)
• Consequence: TTC19 NM_017775.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.31
• Publications: 2 publications found

Genes affected

TTC19 (HGNC:26006): (tetratricopeptide repeat domain 19) This gene encodes a protein with a tetratricopeptide repeat (TPR) domain containing several TPRs of about 34 aa each. These repeats are found in a variety of organisms including bacteria, fungi and plants, and are involved in a variety of functions including protein-protein interactions. This protein is embedded in the inner mitochondrial membrane and is involved in the formation of the mitochondrial respiratory chain III. It has also been suggested that this protein plays a role in cytokinesis. Mutations in this gene cause mitochondrial complex III deficiency. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2012]

TTC19 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex III deficiency nuclear type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial complex III deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-16003114-G-A is Benign according to our data. Variant chr17-16003114-G-A is described in ClinVar as Benign. ClinVar VariationId is 673802.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC19	NM_017775.4	c.462+283G>A		intron_variant	Intron 4 of 9	ENST00000261647.10	NP_060245.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC19	ENST00000261647.10	c.462+283G>A		intron_variant	Intron 4 of 9	1	NM_017775.4	ENSP00000261647.5

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 13284 AN: 152072 Hom.: 1569 Cov.: 32

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.0500

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00894

Gnomad OTH AF: 0.0593

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0876 AC: 13339 AN: 152190 Hom.: 1581 Cov.: 32 AF XY: 0.0859 AC XY: 6391 AN XY: 74434

African (AFR) AF: 0.273 AC: 11303 AN: 41452

American (AMR) AF: 0.0323 AC: 494 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 33 AN: 3468

East Asian (EAS) AF: 0.0503 AC: 260 AN: 5170

South Asian (SAS) AF: 0.100 AC: 485 AN: 4828

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10624

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00894 AC: 608 AN: 68030

Other (OTH) AF: 0.0606 AC: 128 AN: 2112

Alfa AF: 0.0639 Hom.: 139

Bravo AF: 0.0961

Asia WGS AF: 0.100 AC: 349 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.40
PhyloP100		2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2302416; hg19: chr17-15906428;