17-16039518-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_006311.4(NCOR1):c.6870G>A(p.Met2290Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,614,140 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (18 hom.)
• Consequence: NCOR1 NM_006311.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00800

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NCOR1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0032114685).
• BP6: Variant 17-16039518-C-T is Benign according to our data. Variant chr17-16039518-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 722211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOR1	NM_006311.4	c.6870G>A	p.Met2290Ile	missense_variant	44/46	ENST00000268712.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOR1	ENST00000268712.8	c.6870G>A	p.Met2290Ile	missense_variant	44/46	1	NM_006311.4	P3

Frequencies

GnomAD3 genomes AF: 0.000927 AC: 141 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00210 AC: 527 AN: 251472 Hom.: 2 AF XY: 0.00278 AC XY: 378 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0128

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00123 AC: 1804 AN: 1461888 Hom.: 18 Cov.: 31 AF XY: 0.00168 AC XY: 1225 AN XY: 727242

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0137

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000370

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.000926 AC: 141 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74448

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000758 Hom.: 0

Bravo AF: 0.000559

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00249 AC: 302

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NCOR1: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2018	- -

NCOR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 23, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	17
Dann	Benign	0.93
DEOGEN2	Benign	0.30	T;.;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.84	T;T;T;T
MetaRNN	Benign	0.0032	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.21	N;.;N;.
REVEL	Benign	0.025
Sift	Benign	0.16	T;.;T;.
Sift4G	Benign	0.40	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.078
MutPred		0.29		Loss of disorder (P = 0.0474);.;.;.;
MVP		0.40
MPC		0.31
ClinPred		0.010	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.047

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: rs139149781; hg19: chr17-15942832; COSMIC: COSV105098758; COSMIC: COSV105098758;