20-62817087-C-T

Position:

• chr20-62817087-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001853.4(COL9A3):​c.23C>T​(p.Ala8Val) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.697

Genes affected

COL9A3 (HGNC:2219): (collagen type IX alpha 3 chain) This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. Mutations in this gene are associated with multiple epiphyseal dysplasia type 3. [provided by RefSeq, Jan 2010]

COL9A3 (HGNC:):

ACMG classification

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=0.17907277).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A3	NM_001853.4	c.23C>T	p.Ala8Val	missense_variant	1/32	ENST00000649368.1	NP_001844.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1	c.23C>T	p.Ala8Val	missense_variant	1/32		NM_001853.4	ENSP00000496793.1
COL9A3	ENST00000477612.5	n.75-480C>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1244146 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 613676

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 8 of the COL9A3 protein (p.Ala8Val). 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. Advanced 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 COL9A3 protein function. This variant has not been reported in the literature in individuals affected with COL9A3-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.3
DANN	Benign	0.94
DEOGEN2	Benign	0.00089	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.32	.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.1	L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.28	.;N
REVEL	Benign	0.25
Sift	Benign	0.70	.;T
Sift4G	Benign	0.27	.;T
Polyphen		0.81	P;P
Vest4		0.19
MutPred		0.43		Loss of disorder (P = 0.0495);Loss of disorder (P = 0.0495);
MVP		0.74
MPC		0.070
ClinPred		0.33	T
GERP RS		0.10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.050
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs1990951183; hg19: chr20-61448439;