16-67610960-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_006565.4(CTCF):ā€‹c.128A>Gā€‹(p.Asn43Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,536 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

CTCF
NM_006565.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. 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=0.05802256).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CTCFNM_006565.4 linkuse as main transcriptc.128A>G p.Asn43Ser missense_variant 3/12 ENST00000264010.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CTCFENST00000264010.10 linkuse as main transcriptc.128A>G p.Asn43Ser missense_variant 3/121 NM_006565.4 P4P49711-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000122
AC:
3
AN:
245952
Hom.:
0
AF XY:
0.00000753
AC XY:
1
AN XY:
132714
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.94e-7
AC:
1
AN:
1440536
Hom.:
0
Cov.:
31
AF XY:
0.00000140
AC XY:
1
AN XY:
712102
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000256
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 17, 2023The c.128A>G (p.N43S) alteration is located in exon 3 (coding exon 1) of the CTCF gene. This alteration results from a A to G substitution at nucleotide position 128, causing the asparagine (N) at amino acid position 43 to be replaced by a serine (S). 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
0.086
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
18
DANN
Benign
0.85
DEOGEN2
Benign
0.28
T;T;.;.;.;T;T;.;T
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.20
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.88
.;.;D;.;D;.;.;D;D
M_CAP
Benign
0.0026
T
MetaRNN
Benign
0.058
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-0.20
N;N;.;.;.;N;N;.;N
MutationTaster
Benign
1.0
D;N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
0.33
N;.;.;.;.;.;.;.;.
REVEL
Benign
0.097
Sift
Benign
0.30
T;.;.;.;.;.;.;.;.
Sift4G
Benign
0.71
T;.;.;.;.;.;.;.;.
Polyphen
0.0
B;B;.;.;.;B;B;.;B
Vest4
0.22
MutPred
0.14
Gain of glycosylation at N43 (P = 0.0685);Gain of glycosylation at N43 (P = 0.0685);Gain of glycosylation at N43 (P = 0.0685);Gain of glycosylation at N43 (P = 0.0685);Gain of glycosylation at N43 (P = 0.0685);Gain of glycosylation at N43 (P = 0.0685);Gain of glycosylation at N43 (P = 0.0685);Gain of glycosylation at N43 (P = 0.0685);Gain of glycosylation at N43 (P = 0.0685);
MVP
0.41
MPC
0.34
ClinPred
0.041
T
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.026
gMVP
0.47

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: rs750230442; hg19: chr16-67644863; API