NM_003882.4:c.69+2257G>A

Variant names:

• chr8-133193470-G-A
• rs3739262
• NM_003882.4:c.69+2257G>A

Variant summary

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

The NM_003882.4(CCN4):​c.69+2257G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 152,114 control chromosomes in the GnomAD database, including 4,838 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 0.24 (4838 hom., cov: 32)
• Consequence: CCN4 NM_003882.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.387
• Publications: 14 publications found

Genes affected

CCN4 (HGNC:12769): (cellular communication network factor 4) This gene encodes a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family. WNT1 is a member of a family of cysteine-rich, glycosylated signaling proteins that mediate diverse developmental processes. The CTGF family members are characterized by four conserved cysteine-rich domains: insulin-like growth factor-binding domain, von Willebrand factor type C module, thrombospondin domain and C-terminal cystine knot-like domain. This gene may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. It is expressed at a high level in fibroblast cells, and overexpressed in colon tumors. The encoded protein binds to decorin and biglycan, two members of a family of small leucine-rich proteoglycans present in the extracellular matrix of connective tissue, and possibly prevents the inhibitory activity of decorin and biglycan in tumor cell proliferation. It also attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase. It is 83% identical to the mouse protein at the amino acid level. Multiple alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN4	NM_003882.4	c.69+2257G>A		intron_variant	Intron 1 of 4	ENST00000250160.11	NP_003873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN4	ENST00000250160.11	c.69+2257G>A		intron_variant	Intron 1 of 4	1	NM_003882.4	ENSP00000250160.5

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36545 AN: 151996 Hom.: 4835 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.302

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.240 AC: 36568 AN: 152114 Hom.: 4838 Cov.: 32 AF XY: 0.236 AC XY: 17549 AN XY: 74358

African (AFR) AF: 0.151 AC: 6249 AN: 41504

American (AMR) AF: 0.259 AC: 3961 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1285 AN: 3468

East Asian (EAS) AF: 0.132 AC: 684 AN: 5172

South Asian (SAS) AF: 0.263 AC: 1268 AN: 4826

European-Finnish (FIN) AF: 0.181 AC: 1912 AN: 10592

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20116 AN: 67946

Other (OTH) AF: 0.302 AC: 637 AN: 2106

Alfa AF: 0.281 Hom.: 11651

Bravo AF: 0.244

Asia WGS AF: 0.208 AC: 725 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.41
DANN	Benign	0.58
PhyloP100		-0.39
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: rs3739262; hg19: chr8-134205713;