16-67637901-T-G

Variant names:

• chr16-67637901-T-G
• rs6499137
• NM_006565.4:c.*29T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006565.4(CTCF):​c.*29T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.098 in 1,552,148 control chromosomes in the GnomAD database, including 10,100 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2698 hom., cov: 32)
  • Exomes 𝑓: 0.092 (7402 hom.)
• Consequence: CTCF NM_006565.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.500
• Publications: 36 publications found

Genes affected

CTCF (HGNC:13723): (CCCTC-binding factor) This gene is a member of the BORIS + CTCF gene family and encodes a transcriptional regulator protein with 11 highly conserved zinc finger (ZF) domains. This nuclear protein is able to use different combinations of the ZF domains to bind different DNA target sequences and proteins. Depending upon the context of the site, the protein can bind a histone acetyltransferase (HAT)-containing complex and function as a transcriptional activator or bind a histone deacetylase (HDAC)-containing complex and function as a transcriptional repressor. If the protein is bound to a transcriptional insulator element, it can block communication between enhancers and upstream promoters, thereby regulating imprinted expression. Mutations in this gene have been associated with invasive breast cancers, prostate cancers, and Wilms' tumors. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

CTCF Gene-Disease associations (from GenCC):

• intellectual disability-feeding difficulties-developmental delay-microcephaly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 16-67637901-T-G is Benign according to our data. Variant chr16-67637901-T-G is described in ClinVar as Benign. ClinVar VariationId is 1244031.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTCF	NM_006565.4	c.*29T>G		3_prime_UTR_variant	Exon 12 of 12	ENST00000264010.10	NP_006556.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTCF	ENST00000264010.10	c.*29T>G		3_prime_UTR_variant	Exon 12 of 12	1	NM_006565.4	ENSP00000264010.4

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22805 AN: 152094 Hom.: 2672 Cov.: 32

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0829

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0841

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.103 AC: 23287 AN: 225612 AF XY: 0.100

Gnomad AFR exome AF: 0.327

Gnomad AMR exome AF: 0.0551

Gnomad ASJ exome AF: 0.0539

Gnomad EAS exome AF: 0.0128

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.0897

Gnomad OTH exome AF: 0.0884

GnomAD4 exome AF: 0.0923 AC: 129163 AN: 1399936 Hom.: 7402 Cov.: 28 AF XY: 0.0925 AC XY: 64067 AN XY: 692944

African (AFR) AF: 0.348 AC: 11020 AN: 31706

American (AMR) AF: 0.0559 AC: 2021 AN: 36144

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 1196 AN: 23744

East Asian (EAS) AF: 0.0121 AC: 469 AN: 38902

South Asian (SAS) AF: 0.119 AC: 9445 AN: 79370

European-Finnish (FIN) AF: 0.122 AC: 6283 AN: 51554

Middle Eastern (MID) AF: 0.0765 AC: 296 AN: 3870

European-Non Finnish (NFE) AF: 0.0863 AC: 93007 AN: 1077486

Other (OTH) AF: 0.0949 AC: 5426 AN: 57160

GnomAD4 genome AF: 0.150 AC: 22883 AN: 152212 Hom.: 2698 Cov.: 32 AF XY: 0.149 AC XY: 11077 AN XY: 74432

African (AFR) AF: 0.324 AC: 13439 AN: 41506

American (AMR) AF: 0.0826 AC: 1263 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3470

East Asian (EAS) AF: 0.0133 AC: 69 AN: 5186

South Asian (SAS) AF: 0.111 AC: 537 AN: 4830

European-Finnish (FIN) AF: 0.126 AC: 1342 AN: 10610

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0841 AC: 5721 AN: 68012

Other (OTH) AF: 0.125 AC: 263 AN: 2110

Alfa AF: 0.0877 Hom.: 1813

Bravo AF: 0.153

Asia WGS AF: 0.105 AC: 368 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	3.9
DANN	Benign	0.64
PhyloP100		0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs6499137; hg19: chr16-67671804;