NM_006565.4:c.118T>G

Variant names:

• chr16-67610950-T-G
• rs775896161
• NM_006565.4:c.118T>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_006565.4(CTCF):​c.118T>G​(p.Leu40Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000705 in 1,418,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L40F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: CTCF NM_006565.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.304
• Publications: 1 publications found

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]

CTCF Gene-Disease associations (from GenCC):

• intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PP2: Missense variant in the CTCF gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 4.4399 (above the threshold of 3.09). Trascript score misZ: 4.8366 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome, syndromic intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.04353875).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006565.4. 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
	CTCF	NM_006565.4	MANE Select	c.118T>G	p.Leu40Val	missense	Exon 3 of 12	NP_006556.1	P49711-1
	CTCF	NM_001438968.1		c.118T>G	p.Leu40Val	missense	Exon 3 of 12	NP_001425897.1
	CTCF	NM_001363916.2		c.118T>G	p.Leu40Val	missense	Exon 3 of 12	NP_001350845.1	A0A2R8YFL0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTCF	ENST00000264010.10	TSL:1 MANE Select	c.118T>G	p.Leu40Val	missense	Exon 3 of 12	ENSP00000264010.4	P49711-1
	CTCF	ENST00000401394.6	TSL:1	c.-32-5795T>G		intron	N/A	ENSP00000384707.1	P49711-2
	CTCF	ENST00000642819.1		c.118T>G	p.Leu40Val	missense	Exon 2 of 11	ENSP00000494408.1	P49711-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000430 AC: 1 AN: 232638 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000932

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000705 AC: 10 AN: 1418838 Hom.: 0 Cov.: 31 AF XY: 0.00000715 AC XY: 5 AN XY: 699362

African (AFR) AF: 0.00 AC: 0 AN: 32218

American (AMR) AF: 0.00 AC: 0 AN: 39588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24420

East Asian (EAS) AF: 0.00 AC: 0 AN: 38936

South Asian (SAS) AF: 0.00 AC: 0 AN: 80842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00000828 AC: 9 AN: 1086362

Other (OTH) AF: 0.0000171 AC: 1 AN: 58328

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.4
DANN	Benign	0.94
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.30
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.050
Sift	Uncertain	0.017	D
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.22		Gain of catalytic residue at L40 (P = 0.0934)
MVP		0.18
MPC		0.43
ClinPred		0.048	T
GERP RS		-0.031
PromoterAI		-0.0055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.032
gMVP		0.18
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs775896161; hg19: chr16-67644853;