rs189970612

Variant names:

• chr17-16029408-T-C
• rs189970612
• NM_006311.4:c.*2888A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006311.4(NCOR1):​c.*2888A>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 0.000636 in 322,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: NCOR1 NM_006311.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS2: High AC in GnomAd4 at 102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOR1	NM_006311.4	c.*2888A>G		3_prime_UTR_variant	Exon 46 of 46	ENST00000268712.8	NP_006302.2
TTC19	NM_017775.4	c.*1886T>C		downstream_gene_variant		ENST00000261647.10	NP_060245.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOR1	ENST00000268712	c.*2888A>G		3_prime_UTR_variant	Exon 46 of 46	1	NM_006311.4	ENSP00000268712.2
TTC19	ENST00000261647.10	c.*1886T>C		downstream_gene_variant		1	NM_017775.4	ENSP00000261647.5

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000723 AC: 36 AN: 49770 AF XY: 0.000745

Gnomad AFR exome AF: 0.000225

Gnomad AMR exome AF: 0.000423

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.000607 AC: 103 AN: 169804 Hom.: 0 Cov.: 0 AF XY: 0.000507 AC XY: 48 AN XY: 94708

African (AFR) AF: 0.000229 AC: 1 AN: 4368

American (AMR) AF: 0.000248 AC: 2 AN: 8052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4474

East Asian (EAS) AF: 0.00 AC: 0 AN: 7038

South Asian (SAS) AF: 0.0000304 AC: 1 AN: 32918

European-Finnish (FIN) AF: 0.000128 AC: 1 AN: 7842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 602

European-Non Finnish (NFE) AF: 0.000934 AC: 90 AN: 96334

Other (OTH) AF: 0.000978 AC: 8 AN: 8176

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74492

African (AFR) AF: 0.000265 AC: 11 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.000752

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex III deficiency nuclear type 1 Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.2
DANN	Benign	0.57

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: rs189970612; hg19: chr17-15932722; COSMIC: COSV107230640;