6-70217008-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001851.6(COL9A1):​c.2655T>G​(p.Ile885Met) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

COL9A1
NM_001851.6 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.387
Variant links:
Genes affected
COL9A1 (HGNC:2217): (collagen type IX alpha 1 chain) This gene encodes one of the three alpha chains of type IX collagen, which is a minor (5-20%) collagen component of hyaline cartilage. Type IX collagen is usually found in tissues containing type II collagen, a fibrillar collagen. Studies in knockout mice have shown that synthesis of the alpha 1 chain is essential for assembly of type IX collagen molecules, a heterotrimeric molecule, and that lack of type IX collagen is associated with early onset osteoarthritis. Mutations in this gene are associated with osteoarthritis in humans, with multiple epiphyseal dysplasia, 6, a form of chondrodysplasia, and with Stickler syndrome, a disease characterized by ophthalmic, orofacial, articular, and auditory defects. Two transcript variants that encode different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19278958).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL9A1NM_001851.6 linkuse as main transcriptc.2655T>G p.Ile885Met missense_variant 38/38 ENST00000357250.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL9A1ENST00000357250.11 linkuse as main transcriptc.2655T>G p.Ile885Met missense_variant 38/381 NM_001851.6 P1P20849-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 13, 2022Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL9A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with COL9A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 885 of the COL9A1 protein (p.Ile885Met). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Uncertain
0.052
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
16
DANN
Uncertain
0.98
DEOGEN2
Benign
0.10
T;.
Eigen
Benign
-0.063
Eigen_PC
Benign
0.048
FATHMM_MKL
Benign
0.63
D
LIST_S2
Benign
0.84
T;T
M_CAP
Benign
0.078
D
MetaRNN
Benign
0.19
T;T
MetaSVM
Uncertain
-0.25
T
MutationAssessor
Benign
0.91
L;.
MutationTaster
Benign
0.53
D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.080
N;N
REVEL
Benign
0.27
Sift
Benign
0.090
T;T
Sift4G
Benign
0.11
T;T
Polyphen
0.27
B;D
Vest4
0.23
MutPred
0.27
Gain of catalytic residue at I885 (P = 0.0345);.;
MVP
0.94
MPC
0.39
ClinPred
0.52
D
GERP RS
3.4
Varity_R
0.062
gMVP
0.15

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-70926711; API