17-16047086-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.6544G>A(p.Ala2182Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00982 in 1,611,402 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (10 hom., cov: 32)
  • Exomes 𝑓: 0.010 (86 hom.)
• Consequence: NCOR1 NM_006311.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.87

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]

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=0.0074718).
• BP6: Variant 17-16047086-C-T is Benign according to our data. Variant chr17-16047086-C-T is described in ClinVar as [Benign]. Clinvar id is 771023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 1007 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOR1	NM_006311.4	c.6544G>A	p.Ala2182Thr	missense_variant	42/46	ENST00000268712.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOR1	ENST00000268712.8	c.6544G>A	p.Ala2182Thr	missense_variant	42/46	1	NM_006311.4	P3

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 1007 AN: 152148 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00480

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00667 AC: 1641 AN: 245970 Hom.: 7 AF XY: 0.00674 AC XY: 897 AN XY: 133136

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00811

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000766

Gnomad FIN exome AF: 0.00562

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.00961

GnomAD4 exome AF: 0.0102 AC: 14818 AN: 1459136 Hom.: 86 Cov.: 31 AF XY: 0.0100 AC XY: 7275 AN XY: 725810

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.00682

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00100

Gnomad4 FIN exome AF: 0.00613

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.00805

GnomAD4 genome AF: 0.00661 AC: 1007 AN: 152266 Hom.: 10 Cov.: 32 AF XY: 0.00614 AC XY: 457 AN XY: 74456

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00480

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0107 Hom.: 11

Bravo AF: 0.00647

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.00725 AC: 880

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0109

EpiControl AF: 0.0110

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	NCOR1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2018	- -

NCOR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

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	0.086
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	22
Dann	Benign	0.88
DEOGEN2	Benign	0.34	T;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D
MetaRNN	Benign	0.0075	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.030	N;.;N
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.024	D;D;D
Polyphen		0.0	B;.;B
Vest4		0.23
MVP		0.43
MPC		0.28
ClinPred		0.048	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.33

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: rs61753149; hg19: chr17-15950400; COSMIC: COSV51974898; COSMIC: COSV51974898;