NM_003613.4:c.1184T>A

Variant names:

• chr15-65201874-A-T
• rs2073711
• NM_003613.4:c.1184T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003613.4(CILP):​c.1184T>A​(p.Ile395Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. I395T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CILP NM_003613.4 missense, splice_region
• Scores: Splicing: ADA: 0.00002048
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.12
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

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.1184T>A	p.Ile395Lys	missense splice_region	Exon 8 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.1184T>A	p.Ile395Lys	missense splice_region	Exon 8 of 9	ENSP00000261883.4	O75339
	CILP	ENST00000888802.1		c.1190T>A	p.Ile397Lys	missense splice_region	Exon 8 of 9	ENSP00000558861.1
	CILP	ENST00000941157.1		c.1184T>A	p.Ile395Lys	missense splice_region	Exon 8 of 9	ENSP00000611216.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1383246 Hom.: 0 Cov.: 44 AF XY: 0.00 AC XY: 0 AN XY: 683660

African (AFR) AF: 0.00 AC: 0 AN: 29964

American (AMR) AF: 0.00 AC: 0 AN: 34684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23032

East Asian (EAS) AF: 0.00 AC: 0 AN: 35020

South Asian (SAS) AF: 0.00 AC: 0 AN: 74182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073116

Other (OTH) AF: 0.00 AC: 0 AN: 56926

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.21
Sift	Benign	0.14	T
Sift4G	Uncertain	0.023	D
Polyphen		0.059	B
Vest4		0.67
MutPred		0.68		Loss of stability (P = 0.0074)
MVP		0.48
MPC		0.22
ClinPred		0.67	D
GERP RS		3.4
Varity_R		0.18
gMVP		0.87
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
dbscSNV1_RF	Benign	0.0
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: rs2073711; hg19: chr15-65494212;