17-16029111-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017775.4(TTC19):c.*1589T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0326 in 445,342 control chromosomes in the GnomAD database, including 311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (91 hom., cov: 31)
  • Exomes 𝑓: 0.034 (220 hom.)
• Consequence: TTC19 NM_017775.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.913

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]

NCOR1 (HGNC:7672): (nuclear receptor corepressor 1) This gene encodes a protein that mediates ligand-independent transcription repression of thyroid-hormone and retinoic-acid receptors by promoting chromatin condensation and preventing access of the transcription machinery. It is part of a complex which also includes histone deacetylases and transcriptional regulators similar to the yeast protein Sin3p. This gene is located between the Charcot-Marie-Tooth and Smith-Magenis syndrome critical regions on chromosome 17. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 17 and 20.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-16029111-T-C is Benign according to our data. Variant chr17-16029111-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 891562.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0291 (4352/149690) while in subpopulation NFE AF= 0.0435 (2901/66644). AF 95% confidence interval is 0.0422. There are 91 homozygotes in gnomad4. There are 2103 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 91 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTC19	NM_017775.4	c.*1589T>C		3_prime_UTR_variant	10/10	ENST00000261647.10
NCOR1	NM_006311.4			downstream_gene_variant		ENST00000268712.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC19	ENST00000261647.10	c.*1589T>C		3_prime_UTR_variant	10/10	1	NM_017775.4	P1
NCOR1	ENST00000268712.8			downstream_gene_variant		1	NM_006311.4	P3

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 4354 AN: 149568 Hom.: 91 Cov.: 31

Gnomad AFR AF: 0.00843

Gnomad AMI AF: 0.00118

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0510

Gnomad MID AF: 0.0227

Gnomad NFE AF: 0.0435

Gnomad OTH AF: 0.0290

GnomAD3 exomes AF: 0.0290 AC: 3578 AN: 123262 Hom.: 91 AF XY: 0.0297 AC XY: 2009 AN XY: 67548

Gnomad AFR exome AF: 0.00712

Gnomad AMR exome AF: 0.0142

Gnomad ASJ exome AF: 0.0386

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0199

Gnomad FIN exome AF: 0.0544

Gnomad NFE exome AF: 0.0460

Gnomad OTH exome AF: 0.0311

GnomAD4 exome AF: 0.0343 AC: 10150 AN: 295652 Hom.: 220 Cov.: 0 AF XY: 0.0333 AC XY: 5611 AN XY: 168500

Gnomad4 AFR exome AF: 0.00783

Gnomad4 AMR exome AF: 0.0144

Gnomad4 ASJ exome AF: 0.0371

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0204

Gnomad4 FIN exome AF: 0.0540

Gnomad4 NFE exome AF: 0.0448

Gnomad4 OTH exome AF: 0.0346

GnomAD4 genome AF: 0.0291 AC: 4352 AN: 149690 Hom.: 91 Cov.: 31 AF XY: 0.0288 AC XY: 2103 AN XY: 73124

Gnomad4 AFR AF: 0.00833

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.0354

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0196

Gnomad4 FIN AF: 0.0510

Gnomad4 NFE AF: 0.0435

Gnomad4 OTH AF: 0.0287

Alfa AF: 0.0349 Hom.: 30

Bravo AF: 0.0257

Asia WGS AF: 0.00983 AC: 34 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex III deficiency nuclear type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	2.7
Dann	Benign	0.84

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs117133932; hg19: chr17-15932425;