Genetic Variant NM_003882.4:c.*3597C>T (chr8-133231307-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003882.4(CCN4):c.*3597C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.542 in 151,824 control chromosomes in the GnomAD database, including 22,505 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 0.54 ( 22505 hom., cov: 32)

Failed GnomAD Quality Control

Consequence

CCN4
NM_003882.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.437

Publications

9 publications found

Variant links:

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]

CCN4 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=-0.86).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCN4	NM_003882.4 link	c.*3597C>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000250160.11	NP_003873.1	O95388-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCN4	ENST00000250160.11 link	c.*3597C>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_003882.4	ENSP00000250160.5		O95388-1

Frequencies

GnomAD3 genomes

AF:

0.542

AC:

82193

AN:

151706

Hom.:

22489

Cov.:

show subpopulations

Gnomad AFR

AF:

0.614

Gnomad AMI

AF:

0.518

Gnomad AMR

AF:

0.478

Gnomad ASJ

AF:

0.578

Gnomad EAS

AF:

0.611

Gnomad SAS

AF:

0.572

Gnomad FIN

AF:

0.444

Gnomad MID

AF:

0.631

Gnomad NFE

AF:

0.518

Gnomad OTH

AF:

0.544

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.542

AC:

82244

AN:

151824

Hom.:

22505

Cov.:

AF XY:

0.536

AC XY:

39788

AN XY:

74166

show subpopulations

African (AFR)

AF:

0.614

AC:

25401

AN:

41396

American (AMR)

AF:

0.478

AC:

7290

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.578

AC:

2003

AN:

3466

East Asian (EAS)

AF:

0.611

AC:

3150

AN:

5154

South Asian (SAS)

AF:

0.570

AC:

2740

AN:

4808

European-Finnish (FIN)

AF:

0.444

AC:

4666

AN:

10508

Middle Eastern (MID)

AF:

0.630

AC:

184

AN:

292

European-Non Finnish (NFE)

AF:

0.518

AC:

35189

AN:

67930

Other (OTH)

AF:

0.546

AC:

1150

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1949

3897

5846

7794

9743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

714

1428

2142

2856

3570

<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:

0.528

Hom.:

47757

Bravo

AF:

0.547

Asia WGS

AF:

0.576

AC:

2003

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.16

(source)

DANN

Benign

0.31

PhyloP100

-0.44

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over