Genetic Variant CTCFL:c.544-66A>C (chr20-57523344-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001386993.1(CTCFL):c.544-66A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0403 in 1,434,458 control chromosomes in the GnomAD database, including 1,465 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 0.029 ( 110 hom., cov: 33)

Exomes 𝑓: 0.042 ( 1355 hom. )

Consequence

CTCFL
NM_001386993.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.458

Publications

2 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0289 (4398/152322) while in subpopulation NFE AF = 0.0483 (3285/68036). AF 95% confidence interval is 0.0469. There are 110 homozygotes in GnomAd4. There are 1934 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 110 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTCFL	NM_001386993.1 link	c.544-66A>C		intron_variant	Intron 2 of 10	ENST00000243914.8	NP_001373922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTCFL	ENST00000243914.8 link	c.544-66A>C		intron_variant	Intron 2 of 10	1	NM_001386993.1	ENSP00000243914.3		Q8NI51-1

Frequencies

GnomAD3 genomes

AF:

0.0289

AC:

4400

AN:

152204

Hom.:

110

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00787

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.0369

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00910

Gnomad FIN

AF:

0.0202

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0483

Gnomad OTH

AF:

0.0291

GnomAD4 exome

AF:

0.0416

AC:

53339

AN:

1282136

Hom.:

1355

AF XY:

0.0408

AC XY:

26132

AN XY:

640648

show subpopulations

African (AFR)

AF:

0.00731

AC:

210

AN:

28740

American (AMR)

AF:

0.0159

AC:

566

AN:

35508

Ashkenazi Jewish (ASJ)

AF:

0.0324

AC:

738

AN:

22756

East Asian (EAS)

AF:

0.000104

AC:

AN:

38592

South Asian (SAS)

AF:

0.0110

AC:

826

AN:

74834

European-Finnish (FIN)

AF:

0.0217

AC:

1033

AN:

47502

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

3826

European-Non Finnish (NFE)

AF:

0.0490

AC:

47900

AN:

976562

Other (OTH)

AF:

0.0366

AC:

1971

AN:

53816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

2566

5131

7697

10262

12828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1654

3308

4962

6616

8270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0289

AC:

4398

AN:

152322

Hom.:

110

Cov.:

AF XY:

0.0260

AC XY:

1934

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00785

AC:

326

AN:

41554

American (AMR)

AF:

0.0202

AC:

309

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0369

AC:

128

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00911

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0202

AC:

214

AN:

10616

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0483

AC:

3285

AN:

68036

Other (OTH)

AF:

0.0284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

218

437

655

874

1092

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0178

Hom.:

Bravo

AF:

0.0285

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.71

(source)

DANN

Benign

0.67

PhyloP100

-0.46

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over