chr16-67610861-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_006565.4(CTCF):ā€‹c.29T>Cā€‹(p.Val10Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000133 in 1,500,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 7.4e-7 ( 0 hom. )

Consequence

CTCF
NM_006565.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.82
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.09570822).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CTCFNM_006565.4 linkuse as main transcriptc.29T>C p.Val10Ala missense_variant 3/12 ENST00000264010.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CTCFENST00000264010.10 linkuse as main transcriptc.29T>C p.Val10Ala missense_variant 3/121 NM_006565.4 P4P49711-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
7.42e-7
AC:
1
AN:
1348276
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
657590
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.47e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152224
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

CTCF-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 08, 2023The CTCF c.29T>C variant is predicted to result in the amino acid substitution p.Val10Ala. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.31
T;T;.;.;.;T;T;.;T
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.11
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.69
.;.;T;.;T;.;.;T;T
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.096
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.0
L;L;.;.;.;L;L;.;L
MutationTaster
Benign
0.99
D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
0.21
N;.;.;.;.;.;.;.;.
REVEL
Benign
0.036
Sift
Benign
0.038
D;.;.;.;.;.;.;.;.
Sift4G
Uncertain
0.020
D;.;.;.;.;.;.;.;.
Polyphen
0.0
B;B;.;.;.;B;B;.;B
Vest4
0.27
MutPred
0.17
Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP
0.39
MPC
0.52
ClinPred
0.35
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.2
Varity_R
0.035
gMVP
0.30

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1434204599; hg19: chr16-67644764; API