rs9890012

Variant names:

• chr17-16029313-T-C
• rs9890012
• NM_006311.4:c.*2983A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.401
• Publications: 9 publications found

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]

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: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 321984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006311.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOR1	NM_006311.4	MANE Select	c.*2983A>G		3_prime_UTR	Exon 46 of 46	NP_006302.2
	TTC19	NM_017775.4	MANE Select	c.*1791T>C		3_prime_UTR	Exon 10 of 10	NP_060245.3
	NCOR1	NM_001439111.1		c.*2983A>G		3_prime_UTR	Exon 47 of 47	NP_001426040.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOR1	ENST00000268712.8	TSL:1 MANE Select	c.*2983A>G		3_prime_UTR	Exon 46 of 46	ENSP00000268712.2	O75376-1
	TTC19	ENST00000261647.10	TSL:1 MANE Select	c.*1791T>C		3_prime_UTR	Exon 10 of 10	ENSP00000261647.5	Q6DKK2
	NCOR1	ENST00000436068.2	TSL:1	c.*2983A>G		3_prime_UTR	Exon 47 of 47	ENSP00000389839.2	H0Y459

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

GnomAD2 exomes AF: 0.453 AC: 55019 AN: 121336 AF XY: 0.457

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 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

African (AFR) AF: 0.388 AC: 3145 AN: 8100

American (AMR) AF: 0.383 AC: 9902 AN: 25842

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 6589 AN: 10482

East Asian (EAS) AF: 0.138 AC: 1258 AN: 9106

South Asian (SAS) AF: 0.392 AC: 22153 AN: 56502

European-Finnish (FIN) AF: 0.560 AC: 6834 AN: 12210

Middle Eastern (MID) AF: 0.572 AC: 637 AN: 1114

European-Non Finnish (NFE) AF: 0.535 AC: 82724 AN: 154568

Other (OTH) AF: 0.501 AC: 6851 AN: 13666

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

African (AFR) AF: 0.391 AC: 16223 AN: 41454

American (AMR) AF: 0.465 AC: 7096 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.640 AC: 2218 AN: 3468

East Asian (EAS) AF: 0.145 AC: 750 AN: 5176

South Asian (SAS) AF: 0.372 AC: 1788 AN: 4800

European-Finnish (FIN) AF: 0.563 AC: 5933 AN: 10530

Middle Eastern (MID) AF: 0.565 AC: 165 AN: 292

European-Non Finnish (NFE) AF: 0.538 AC: 36565 AN: 67934

Other (OTH) AF: 0.493 AC: 1043 AN: 2114

Alfa AF: 0.517 Hom.: 4382

Bravo AF: 0.463

Asia WGS AF: 0.302 AC: 1050 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Mitochondrial complex III deficiency nuclear type 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.8
DANN	Benign	0.78
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9890012; hg19: chr17-15932627;