rs750230442

Variant names:

• chr16-67610960-A-G
• rs750230442
• NM_006565.4:c.128A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_006565.4(CTCF):​c.128A>G​(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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CTCF NM_006565.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.05802256).

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.128A>G	p.Asn43Ser	missense	Exon 3 of 12	NP_006556.1	P49711-1
	CTCF	NM_001438968.1		c.128A>G	p.Asn43Ser	missense	Exon 3 of 12	NP_001425897.1
	CTCF	NM_001363916.2		c.128A>G	p.Asn43Ser	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.128A>G	p.Asn43Ser	missense	Exon 3 of 12	ENSP00000264010.4	P49711-1
	CTCF	ENST00000401394.6	TSL:1	c.-32-5785A>G		intron	N/A	ENSP00000384707.1	P49711-2
	CTCF	ENST00000642819.1		c.128A>G	p.Asn43Ser	missense	Exon 2 of 11	ENSP00000494408.1	P49711-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245952 AF XY: 0.00000753

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33062

American (AMR) AF: 0.00 AC: 0 AN: 43830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25476

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39136

South Asian (SAS) AF: 0.00 AC: 0 AN: 84956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095984

Other (OTH) AF: 0.00 AC: 0 AN: 59328

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.20	N
PhyloP100		2.3
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
Vest4		0.22
MutPred		0.14		Gain of glycosylation at N43 (P = 0.0685)
MVP		0.41
MPC		0.34
ClinPred		0.041	T
GERP RS		4.1
PromoterAI		-0.0036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.026
gMVP		0.47
Mutation Taster		=95/5	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: rs750230442; hg19: chr16-67644863;