20-57518856-C-T

Variant summary

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

The NM_001386993.1(CTCFL):c.961G>A(p.Ala321Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTCFL NM_001386993.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

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]

ACMG classification

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	c.961G>A	p.Ala321Thr	missense_variant	5/11	ENST00000243914.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTCFL	ENST00000243914.8	c.961G>A	p.Ala321Thr	missense_variant	5/11	1	NM_001386993.1	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.961G>A (p.A321T) alteration is located in exon 5 (coding exon 4) of the CTCFL gene. This alteration results from a G to A substitution at nucleotide position 961, causing the alanine (A) at amino acid position 321 to be replaced by a threonine (T). 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	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;.;D;.;D;D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.49	N;N;N;N;N;N;N;.;.;N;.;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.0	D;.;.;D;D;D;.;D;.;D;D;.;D;.;.;.
REVEL	Uncertain	0.29
Sift	Benign	0.054	T;.;.;D;D;D;.;T;.;D;D;.;D;.;.;.
Sift4G	Benign	0.094	T;T;T;T;T;T;T;T;T;D;T;T;T;T;D;D
Polyphen		1.0	.;D;D;.;D;D;.;.;.;.;.;.;.;.;.;.
Vest4		0.71
MutPred		0.47		Loss of catalytic residue at A321 (P = 0.0395);Loss of catalytic residue at A321 (P = 0.0395);Loss of catalytic residue at A321 (P = 0.0395);Loss of catalytic residue at A321 (P = 0.0395);Loss of catalytic residue at A321 (P = 0.0395);Loss of catalytic residue at A321 (P = 0.0395);Loss of catalytic residue at A321 (P = 0.0395);.;.;Loss of catalytic residue at A321 (P = 0.0395);.;.;Loss of catalytic residue at A321 (P = 0.0395);Loss of catalytic residue at A321 (P = 0.0395);Loss of catalytic residue at A321 (P = 0.0395);Loss of catalytic residue at A321 (P = 0.0395);
MVP		0.47
MPC		1.4
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.42

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: rs995538553; hg19: chr20-56093912; COSMIC: COSV99712047;