dbSNP rs6070122: CTCFL:p.Gln525Glu (chr20-57508707-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.018 ( 38 hom., cov: 32)

Exomes 𝑓: 0.023 ( 481 hom. )

Consequence

CTCFL
NM_001386993.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.77

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 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 rank	MANE	Protein	UniProt
CTCFL	NM_001386993.1 link	c.1573C>G	p.Gln525Glu	missense_variant	Exon 9 of 11	ENST00000243914.8	NP_001373922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTCFL	ENST00000243914.8 link	c.1573C>G	p.Gln525Glu	missense_variant	Exon 9 of 11	1	NM_001386993.1	ENSP00000243914.3		Q8NI51-1

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2745

AN:

152162

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0198

AC XY:

2696

AN XY:

135914

show subpopulations

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.:

AF XY:

0.0225

AC XY:

16337

AN XY:

727234

show subpopulations

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.:

Cov.:

AF XY:

0.0190

AC XY:

1418

AN XY:

74464

show subpopulations

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.:

Bravo

AF:

0.0133

TwinsUK

AF:

0.0232

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0242

AC:

208

ExAC

AF:

0.0197

AC:

2394

Asia WGS

AF:

0.00144

AC:

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

BayesDel_noAF

Benign

-0.18

CADD

Pathogenic

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

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

MutationAssessor

Benign

1.6

L;L;L;.;L;L;L;.;.;.;.;.;L;.

PrimateAI

Benign

0.46

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

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over