rs6025606

chr20-57523677-T-Achr20-57523677-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001386993.1(CTCFL):c.529A>T(p.Thr177Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,218 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T177A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CTCFL NM_001386993.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.28

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057658583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTCFL	NM_001386993.1	c.529A>T	p.Thr177Ser	missense_variant	2/11	ENST00000243914.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTCFL	ENST00000243914.8	c.529A>T	p.Thr177Ser	missense_variant	2/11	1	NM_001386993.1	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248616 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134574

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: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461100 Hom.: 0 Cov.: 51 AF XY: 0.00000688 AC XY: 5 AN XY: 726804

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: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74302

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.0020
Dann	Benign	0.45
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.18	T;.;.;T;.;T;T;T;T;T;.;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.058	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.20	N;N;N;N;N;N;N;N;N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.13	N;.;.;N;N;N;.;N;N;.;.;.
REVEL	Benign	0.028
Sift	Benign	0.39	T;.;.;T;T;T;.;T;T;.;.;.
Sift4G	Benign	0.69	T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;B;B;.;B;B;.;.;.;.;.;.
Vest4		0.041
MutPred		0.25		Gain of glycosylation at T177 (P = 0.0269);Gain of glycosylation at T177 (P = 0.0269);Gain of glycosylation at T177 (P = 0.0269);Gain of glycosylation at T177 (P = 0.0269);Gain of glycosylation at T177 (P = 0.0269);Gain of glycosylation at T177 (P = 0.0269);Gain of glycosylation at T177 (P = 0.0269);Gain of glycosylation at T177 (P = 0.0269);Gain of glycosylation at T177 (P = 0.0269);Gain of glycosylation at T177 (P = 0.0269);Gain of glycosylation at T177 (P = 0.0269);Gain of glycosylation at T177 (P = 0.0269);
MVP		0.33
MPC		0.034
ClinPred		0.041	T
GERP RS		-6.6
Varity_R		0.026
gMVP		0.055

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

Other links and lift over

dbSNP: rs6025606; hg19: chr20-56098733;