chr20-57523677-T-C

Variant names:

• chr20-57523677-T-C
• rs6025606
• NM_001386993.1:c.529A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001386993.1(CTCFL):​c.529A>G​(p.Thr177Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 1,613,034 control chromosomes in the GnomAD database, including 337,491 homozygotes. 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.

• Frequency:
  • Genomes: 𝑓 0.70 (38813 hom., cov: 33)
  • Exomes 𝑓: 0.64 (298678 hom.)
• Consequence: CTCFL NM_001386993.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.28
• Publications: 38 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=1.0147996E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.877 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001386993.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTCFL	NM_001386993.1	MANE Select	c.529A>G	p.Thr177Ala	missense	Exon 2 of 11	NP_001373922.1
	CTCFL	NM_001269043.2		c.529A>G	p.Thr177Ala	missense	Exon 2 of 12	NP_001255972.1
	CTCFL	NM_001269044.3		c.529A>G	p.Thr177Ala	missense	Exon 1 of 10	NP_001255973.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTCFL	ENST00000243914.8	TSL:1 MANE Select	c.529A>G	p.Thr177Ala	missense	Exon 2 of 11	ENSP00000243914.3
	CTCFL	ENST00000423479.7	TSL:1	c.529A>G	p.Thr177Ala	missense	Exon 2 of 12	ENSP00000415579.2
	CTCFL	ENST00000608440.5	TSL:1	c.529A>G	p.Thr177Ala	missense	Exon 1 of 10	ENSP00000477488.1

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106982 AN: 152080 Hom.: 38774 Cov.: 33

Gnomad AFR AF: 0.885

Gnomad AMI AF: 0.535

Gnomad AMR AF: 0.677

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.739

Gnomad SAS AF: 0.660

Gnomad FIN AF: 0.559

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.625

Gnomad OTH AF: 0.720

GnomAD2 exomes AF: 0.656 AC: 163185 AN: 248616 AF XY: 0.651

Gnomad AFR exome AF: 0.890

Gnomad AMR exome AF: 0.650

Gnomad ASJ exome AF: 0.657

Gnomad EAS exome AF: 0.735

Gnomad FIN exome AF: 0.561

Gnomad NFE exome AF: 0.632

Gnomad OTH exome AF: 0.649

GnomAD4 exome AF: 0.637 AC: 931083 AN: 1460836 Hom.: 298678 Cov.: 51 AF XY: 0.637 AC XY: 462573 AN XY: 726684

African (AFR) AF: 0.897 AC: 30032 AN: 33478

American (AMR) AF: 0.654 AC: 29241 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 17220 AN: 26114

East Asian (EAS) AF: 0.733 AC: 29098 AN: 39700

South Asian (SAS) AF: 0.647 AC: 55737 AN: 86212

European-Finnish (FIN) AF: 0.566 AC: 29928 AN: 52858

Middle Eastern (MID) AF: 0.727 AC: 4192 AN: 5766

European-Non Finnish (NFE) AF: 0.626 AC: 695766 AN: 1111626

Other (OTH) AF: 0.660 AC: 39869 AN: 60372

GnomAD4 genome AF: 0.703 AC: 107071 AN: 152198 Hom.: 38813 Cov.: 33 AF XY: 0.699 AC XY: 52042 AN XY: 74412

African (AFR) AF: 0.885 AC: 36789 AN: 41566

American (AMR) AF: 0.676 AC: 10340 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2273 AN: 3466

East Asian (EAS) AF: 0.738 AC: 3825 AN: 5180

South Asian (SAS) AF: 0.658 AC: 3178 AN: 4828

European-Finnish (FIN) AF: 0.559 AC: 5914 AN: 10574

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.625 AC: 42507 AN: 67978

Other (OTH) AF: 0.724 AC: 1531 AN: 2114

Alfa AF: 0.656 Hom.: 138820

Bravo AF: 0.722

TwinsUK AF: 0.626 AC: 2323

ALSPAC AF: 0.623 AC: 2400

ESP6500AA AF: 0.877 AC: 3866

ESP6500EA AF: 0.632 AC: 5431

ExAC AF: 0.662 AC: 80327

Asia WGS AF: 0.687 AC: 2391 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0020
DANN	Benign	0.38
DEOGEN2	Benign	0.044	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		-3.3
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.013
Sift	Benign	0.56	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.0090
MPC		0.036
ClinPred		0.0067	T
GERP RS		-6.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.061
Mutation Taster		=100/0	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: rs6025606; hg19: chr20-56098733; COSMIC: COSV54772270;