rs6070122

Positions:

• chr20-57508707-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001386993.1(CTCFL):​c.1573C>G​(p.Gln525Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,614,114 control chromosomes in the GnomAD database, including 519 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (38 hom., cov: 32)
  • Exomes 𝑓: 0.023 (481 hom.)
• Consequence: CTCFL NM_001386993.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054570436).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.018 (2745/152280) while in subpopulation NFE AF= 0.0253 (1719/68018). AF 95% confidence interval is 0.0243. There are 38 homozygotes in gnomad4. There are 1418 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 38 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTCFL	NM_001386993.1	c.1573C>G	p.Gln525Glu	missense_variant	9/11	ENST00000243914.8	NP_001373922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTCFL	ENST00000243914.8	c.1573C>G	p.Gln525Glu	missense_variant	9/11	1	NM_001386993.1	ENSP00000243914.3

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2745 AN: 152162 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.00714

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0197 AC: 4942 AN: 251474 Hom.: 84 AF XY: 0.0198 AC XY: 2696 AN XY: 135914

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.00674

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00882

Gnomad FIN exome AF: 0.0544

Gnomad NFE exome AF: 0.0260

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0230 AC: 33686 AN: 1461834 Hom.: 481 Cov.: 31 AF XY: 0.0225 AC XY: 16337 AN XY: 727234

Gnomad4 AFR exome AF: 0.00332

Gnomad4 AMR exome AF: 0.00671

Gnomad4 ASJ exome AF: 0.0121

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00927

Gnomad4 FIN exome AF: 0.0555

Gnomad4 NFE exome AF: 0.0252

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0180 AC: 2745 AN: 152280 Hom.: 38 Cov.: 32 AF XY: 0.0190 AC XY: 1418 AN XY: 74464

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.00713

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00767

Gnomad4 FIN AF: 0.0612

Gnomad4 NFE AF: 0.0253

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0222 Hom.: 12

Bravo AF: 0.0133

TwinsUK AF: 0.0232 AC: 86

ALSPAC AF: 0.0218 AC: 84

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0242 AC: 208

ExAC AF: 0.0197 AC: 2394

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0226

EpiControl AF: 0.0234

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T;T;.;T;T;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;.;.;D;.;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0055	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.6	L;L;L;.;L;L;L;.;.;.;.;.;L;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.0	D;.;.;D;D;D;.;D;.;N;D;.;D;.
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D;.;.;D;D;D;.;D;.;T;T;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;T;D;T;T;T;D;D
Polyphen		0.99	.;D;D;.;D;D;.;.;.;.;.;.;.;.
Vest4		0.24
MPC		1.5
ClinPred		0.016	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.54
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: rs6070122; hg19: chr20-56083763;