rs754958

Variant names:

• chr8-133226528-G-A
• rs754958
• NM_003882.4:c.805-883G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-133226528-G-A
• chr8-133226528-G-T

Variant summary

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

The NM_003882.4(CCN4):​c.805-883G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 151,998 control chromosomes in the GnomAD database, including 45,879 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 0.77 (45879 hom., cov: 32)
• Consequence: CCN4 NM_003882.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0720
• Publications: 9 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.818 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003882.4. 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
	CCN4	NM_003882.4	MANE Select	c.805-883G>A		intron	N/A	NP_003873.1
	CCN4	NM_080838.3		c.544-883G>A		intron	N/A	NP_543028.1
	CCN4	NM_001204869.2		c.350-883G>A		intron	N/A	NP_001191798.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCN4	ENST00000250160.11	TSL:1 MANE Select	c.805-883G>A		intron	N/A	ENSP00000250160.5
	CCN4	ENST00000220856.6	TSL:1	c.544-883G>A		intron	N/A	ENSP00000220856.6
	CCN4	ENST00000517423.5	TSL:1	c.350-883G>A		intron	N/A	ENSP00000427744.1

Frequencies

GnomAD3 genomes AF: 0.774 AC: 117625 AN: 151880 Hom.: 45863 Cov.: 32

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.931

Gnomad AMR AF: 0.775

Gnomad ASJ AF: 0.881

Gnomad EAS AF: 0.676

Gnomad SAS AF: 0.786

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.892

Gnomad NFE AF: 0.823

Gnomad OTH AF: 0.791

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

GnomAD4 genome AF: 0.774 AC: 117688 AN: 151998 Hom.: 45879 Cov.: 32 AF XY: 0.766 AC XY: 56908 AN XY: 74292

African (AFR) AF: 0.716 AC: 29659 AN: 41406

American (AMR) AF: 0.775 AC: 11845 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.881 AC: 3060 AN: 3472

East Asian (EAS) AF: 0.676 AC: 3504 AN: 5182

South Asian (SAS) AF: 0.785 AC: 3781 AN: 4818

European-Finnish (FIN) AF: 0.671 AC: 7053 AN: 10510

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.823 AC: 56009 AN: 68018

Other (OTH) AF: 0.791 AC: 1670 AN: 2112

Alfa AF: 0.762 Hom.: 16782

Bravo AF: 0.781

Asia WGS AF: 0.713 AC: 2481 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.62
PhyloP100		0.072
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: rs754958; hg19: chr8-134238771;