Variant 20-57515735-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001386993.1(CTCFL):c.1159C>T(p.Arg387Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CTCFL
NM_001386993.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.03

Variant links:

Genes affected

CTCFL (HGNC:16234): (CCCTC-binding factor like) CCCTC-binding factor (CTCF), an 11-zinc-finger factor involved in gene regulation, utilizes different zinc fingers to bind varying DNA target sites. CTCF forms methylation-sensitive insulators that regulate X-chromosome inactivation. This gene is a paralog of CTCF and appears to be expressed primarily in the cytoplasm of spermatocytes, unlike CTCF which is expressed primarily in the nucleus of somatic cells. CTCF and the protein encoded by this gene are normally expressed in a mutually exclusive pattern that correlates with resetting of methylation marks during male germ cell differentiation. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2012]

CTCFL links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTCFL	NM_001386993.1 linkuse as main transcript	c.1159C>T	p.Arg387Cys	missense_variant	6/11	ENST00000243914.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTCFL	ENST00000243914.8 linkuse as main transcript	c.1159C>T	p.Arg387Cys	missense_variant	6/11	1	NM_001386993.1	P4	Q8NI51-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251484

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Apr 21, 2023

A homozygous missense variation in exon 6 of the CTCFL gene that results in the amino acid substitution of Cystine for Arginine at codon 387 was detected. The variant c.1159C>T (p.Arg387Cys) was not observed in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by SIFT, DANN, PROVEAN and MetaRNN. The variant was also observed in heterozygous state in unaffected father.In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

0.98

D;.;.;D;.;D;D;D;D;D;D;D;D

M_CAP

Benign

0.076

MetaRNN

Uncertain

0.66

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.8

M;M;M;M;M;M;M;.;.;.;.;M;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.5

D;.;.;D;D;D;.;D;.;D;.;D;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

D;.;.;D;D;D;.;D;.;D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;D;D;.;D;D;.;.;.;.;.;.;.

Vest4

0.80

MutPred

0.44

Loss of MoRF binding (P = 0.0053);Loss of MoRF binding (P = 0.0053);Loss of MoRF binding (P = 0.0053);Loss of MoRF binding (P = 0.0053);Loss of MoRF binding (P = 0.0053);Loss of MoRF binding (P = 0.0053);Loss of MoRF binding (P = 0.0053);.;.;.;.;Loss of MoRF binding (P = 0.0053);Loss of MoRF binding (P = 0.0053);

MVP

0.56

MPC

1.7

ClinPred

0.99

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.49

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over