16-67610952-A-T

Position:

• chr16-67610952-A-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.120A>T​(p.Leu40Phe) 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. 14/21 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. L40V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTCF NM_006565.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.393

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 in gene, where missense usually causes diseases (based on misZ statistic), CTCF. . Gene score misZ 4.4399 (greater than the threshold 3.09). Trascript score misZ 4.8366 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, syndromic intellectual disability, intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06971827).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTCF	NM_006565.4	c.120A>T	p.Leu40Phe	missense_variant	3/12	ENST00000264010.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTCF	ENST00000264010.10	c.120A>T	p.Leu40Phe	missense_variant	3/12	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

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.120A>T (p.L40F) alteration is located in exon 3 (coding exon 1) of the CTCF gene. This alteration results from a A to T substitution at nucleotide position 120, causing the leucine (L) at amino acid position 40 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T;.;.;.;T;T;.;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.90	.;.;D;.;D;.;.;D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.070	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.0	N;N;.;.;.;N;N;.;N
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.76	N;.;.;.;.;.;.;.;.
REVEL	Benign	0.093
Sift	Uncertain	0.015	D;.;.;.;.;.;.;.;.
Sift4G	Benign	0.31	T;.;.;.;.;.;.;.;.
Polyphen		0.010	B;B;.;.;.;B;B;.;B
Vest4		0.27
MutPred		0.19		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.26
MPC		0.47
ClinPred		0.16	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.051
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-67644855;