15-65197191-C-T

Variant names:

• chr15-65197191-C-T
• rs768702821
• NM_003613.4:c.3095G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003613.4(CILP):​c.3095G>A​(p.Ser1032Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1032T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CILP NM_003613.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.30
• Publications: 0 publications found

Genes affected

CILP (HGNC:1980): (cartilage intermediate layer protein) Major alterations in the composition of the cartilage extracellular matrix occur in joint disease, such as osteoarthrosis. This gene encodes the cartilage intermediate layer protein (CILP), which increases in early osteoarthrosis cartilage. The encoded protein was thought to encode a protein precursor for two different proteins; an N-terminal CILP and a C-terminal homolog of NTPPHase, however, later studies identified no nucleotide pyrophosphatase phosphodiesterase (NPP) activity. The full-length and the N-terminal domain of this protein was shown to function as an IGF-1 antagonist. An allelic variant of this gene has been associated with lumbar disc disease. [provided by RefSeq, Sep 2010]

ENSG00000299580 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21216321).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003613.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CILP	NM_003613.4	MANE Select	c.3095G>A	p.Ser1032Asn	missense	Exon 9 of 9	NP_003604.4	O75339

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CILP	ENST00000261883.6	TSL:1 MANE Select	c.3095G>A	p.Ser1032Asn	missense	Exon 9 of 9	ENSP00000261883.4	O75339
	CILP	ENST00000888802.1		c.3101G>A	p.Ser1034Asn	missense	Exon 9 of 9	ENSP00000558861.1
	CILP	ENST00000941157.1		c.3095G>A	p.Ser1032Asn	missense	Exon 9 of 9	ENSP00000611216.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 77

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.054	T
Eigen	Benign	0.051
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.12
Sift	Benign	0.31	T
Sift4G	Benign	0.36	T
Polyphen		0.18	B
Vest4		0.10
MutPred		0.24		Loss of phosphorylation at S1032 (P = 0.0665)
MVP		0.41
MPC		0.53
ClinPred		0.63	D
GERP RS		5.4
Varity_R		0.23
gMVP		0.59

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: rs768702821; hg19: chr15-65489529;