rs6070122

Variant names:

• chr20-57508707-G-C
• rs6070122
• NM_001386993.1:c.1573C>G

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTCFL	NM_001386993.1	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	c.1573C>G	p.Gln525Glu	missense_variant	Exon 9 of 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

GnomAD2 exomes AF: 0.0197 AC: 4942 AN: 251474 AF XY: 0.0198

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 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

African (AFR) AF: 0.00332 AC: 111 AN: 33478

American (AMR) AF: 0.00671 AC: 300 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 315 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00927 AC: 800 AN: 86258

European-Finnish (FIN) AF: 0.0555 AC: 2963 AN: 53420

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.0252 AC: 28040 AN: 1111958

Other (OTH) AF: 0.0186 AC: 1122 AN: 60396

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

African (AFR) AF: 0.00327 AC: 136 AN: 41562

American (AMR) AF: 0.00713 AC: 109 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4826

European-Finnish (FIN) AF: 0.0612 AC: 649 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0253 AC: 1719 AN: 68018

Other (OTH) AF: 0.0133 AC: 28 AN: 2108

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;.
PhyloP100		7.8
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6070122; hg19: chr20-56083763;