16-67610950-T-G

Position:

• chr16-67610950-T-G

Variant summary

Our verdict is Benign. Variant got -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. 15/21 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. 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

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 Benign. Variant got -7 ACMG points.

• 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=0.04353875).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTCF	NM_006565.4	c.118T>G	p.Leu40Val	missense_variant	3/12	ENST00000264010.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTCF	ENST00000264010.10	c.118T>G	p.Leu40Val	missense_variant	3/12	1	NM_006565.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000430 AC: 1 AN: 232638 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 125584

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 SAS 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

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: 0.00000828

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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

Revvity Omics, Revvity

Jan 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;.;T;T;.;T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.83	.;.;T;.;T;.;.;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.044	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.69	N;N;.;.;.;N;N;.;N
MutationTaster	Benign	1.0	D;N
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;B;.;.;.;B;B;.;B
Vest4		0.17
MutPred		0.22		Gain of catalytic residue at L40 (P = 0.0934);Gain of catalytic residue at L40 (P = 0.0934);Gain of catalytic residue at L40 (P = 0.0934);Gain of catalytic residue at L40 (P = 0.0934);Gain of catalytic residue at L40 (P = 0.0934);Gain of catalytic residue at L40 (P = 0.0934);Gain of catalytic residue at L40 (P = 0.0934);Gain of catalytic residue at L40 (P = 0.0934);Gain of catalytic residue at L40 (P = 0.0934);
MVP		0.18
MPC		0.43
ClinPred		0.048	T
GERP RS		-0.031
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.032
gMVP		0.18

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: rs775896161; hg19: chr16-67644853;