20-57498674-G-A

Variant names:

• chr20-57498674-G-A
• rs780325284
• NM_001386993.1:c.1868C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001386993.1(CTCFL):​c.1868C>T​(p.Thr623Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. T623K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CTCFL NM_001386993.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051990718).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTCFL	NM_001386993.1	MANE Select	c.1868C>T	p.Thr623Met	missense	Exon 11 of 11	NP_001373922.1	Q8NI51-1
	CTCFL	NM_001269043.2		c.1868C>T	p.Thr623Met	missense	Exon 11 of 12	NP_001255972.1	Q8NI51-7
	CTCFL	NM_001269040.2		c.1868C>T	p.Thr623Met	missense	Exon 11 of 11	NP_001255969.1	Q8NI51-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTCFL	ENST00000243914.8	TSL:1 MANE Select	c.1868C>T	p.Thr623Met	missense	Exon 11 of 11	ENSP00000243914.3	Q8NI51-1
	CTCFL	ENST00000423479.7	TSL:1	c.1868C>T	p.Thr623Met	missense	Exon 11 of 12	ENSP00000415579.2	Q8NI51-7
	CTCFL	ENST00000371196.6	TSL:1	c.1868C>T	p.Thr623Met	missense	Exon 11 of 11	ENSP00000360239.2	Q8NI51-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250870 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461516 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727026

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.0020
DANN	Benign	0.58
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.5
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.0090
Sift	Benign	0.35	T
Sift4G	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.094
MutPred		0.24		Gain of loop (P = 0.0097)
MVP		0.068
MPC		0.55
ClinPred		0.043	T
GERP RS		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.015
gMVP		0.076
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs780325284; hg19: chr20-56073730;