17-16029313-T-C

Position:

• chr17-16029313-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006311.4(NCOR1):​c.*2983A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 443,510 control chromosomes in the GnomAD database, including 53,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.48 (17890 hom., cov: 31)
  • Exomes 𝑓: 0.48 (35310 hom.)
• Consequence: NCOR1 NM_006311.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.401

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 17-16029313-T-C is Benign according to our data. Variant chr17-16029313-T-C is described in ClinVar as [Benign]. Clinvar id is 321984.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOR1	NM_006311.4	c.*2983A>G		3_prime_UTR_variant	46/46	ENST00000268712.8
TTC19	NM_017775.4	c.*1791T>C		3_prime_UTR_variant	10/10	ENST00000261647.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTC19	ENST00000261647.10	c.*1791T>C		3_prime_UTR_variant	10/10	1	NM_017775.4	P1
NCOR1	ENST00000268712.8	c.*2983A>G		3_prime_UTR_variant	46/46	1	NM_006311.4	P3

Frequencies

GnomAD3 genomes AF: 0.476 AC: 72201 AN: 151802 Hom.: 17879 Cov.: 31

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.371

Gnomad FIN AF: 0.563

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.490

GnomAD3 exomes AF: 0.453 AC: 55019 AN: 121336 Hom.: 13533 AF XY: 0.457 AC XY: 30263 AN XY: 66248

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.636

Gnomad EAS exome AF: 0.141

Gnomad SAS exome AF: 0.391

Gnomad FIN exome AF: 0.568

Gnomad NFE exome AF: 0.542

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.480 AC: 140093 AN: 291590 Hom.: 35310 Cov.: 0 AF XY: 0.476 AC XY: 78809 AN XY: 165732

Gnomad4 AFR exome AF: 0.388

Gnomad4 AMR exome AF: 0.383

Gnomad4 ASJ exome AF: 0.629

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.392

Gnomad4 FIN exome AF: 0.560

Gnomad4 NFE exome AF: 0.535

Gnomad4 OTH exome AF: 0.501

GnomAD4 genome AF: 0.476 AC: 72256 AN: 151920 Hom.: 17890 Cov.: 31 AF XY: 0.471 AC XY: 34972 AN XY: 74242

Gnomad4 AFR AF: 0.391

Gnomad4 AMR AF: 0.465

Gnomad4 ASJ AF: 0.640

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.372

Gnomad4 FIN AF: 0.563

Gnomad4 NFE AF: 0.538

Gnomad4 OTH AF: 0.493

Alfa AF: 0.520 Hom.: 4310

Bravo AF: 0.463

Asia WGS AF: 0.302 AC: 1050 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex III deficiency nuclear type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.8
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs9890012; hg19: chr17-15932627;