rs146712579

chr16-67637827-C-Achr16-67637827-C-Gchr16-67637827-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006565.4(CTCF):c.2139C>A(p.Asn713Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N713N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTCF NM_006565.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.22

Genes affected

CTCF (HGNC:13723): (CCCTC-binding factor) This gene is a member of the BORIS + CTCF gene family and encodes a transcriptional regulator protein with 11 highly conserved zinc finger (ZF) domains. This nuclear protein is able to use different combinations of the ZF domains to bind different DNA target sequences and proteins. Depending upon the context of the site, the protein can bind a histone acetyltransferase (HAT)-containing complex and function as a transcriptional activator or bind a histone deacetylase (HDAC)-containing complex and function as a transcriptional repressor. If the protein is bound to a transcriptional insulator element, it can block communication between enhancers and upstream promoters, thereby regulating imprinted expression. Mutations in this gene have been associated with invasive breast cancers, prostate cancers, and Wilms' tumors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CTCF
• BP4: Computational evidence support a benign effect (MetaRNN=0.082888275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTCF	NM_006565.4	c.2139C>A	p.Asn713Lys	missense_variant	12/12	ENST00000264010.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTCF	ENST00000264010.10	c.2139C>A	p.Asn713Lys	missense_variant	12/12	1	NM_006565.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Aug 05, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	9.3
Dann	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T;.;.;T;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.083	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.0	L;L;.;.;L;L;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.82	N;.;N;.;.;.;.;.
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.
Sift4G	Uncertain	0.014	D;.;D;.;.;.;.;.
Polyphen		0.27	B;B;.;.;B;B;.;B
Vest4		0.28
MutPred		0.15		Gain of ubiquitination at N713 (P = 0.001);Gain of ubiquitination at N713 (P = 0.001);.;.;Gain of ubiquitination at N713 (P = 0.001);Gain of ubiquitination at N713 (P = 0.001);.;Gain of ubiquitination at N713 (P = 0.001);
MVP		0.46
MPC		0.71
ClinPred		0.88	D
GERP RS		-7.1
Varity_R		0.43
gMVP		0.67

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: rs146712579; hg19: chr16-67671730;