20-62817075-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_001853.4(COL9A3):c.11C>T(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,384,966 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.141

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17474148).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000264 (4/151266) while in subpopulation EAS AF= 0.000775 (4/5160). AF 95% confidence interval is 0.000265. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A3	NM_001853.4	c.11C>T	p.Pro4Leu	missense_variant	1/32	ENST00000649368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A3	ENST00000649368.1	c.11C>T	p.Pro4Leu	missense_variant	1/32		NM_001853.4	P1
COL9A3	ENST00000477612.5	n.75-492C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151266 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000775

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000105 AC: 13 AN: 1233700 Hom.: 0 Cov.: 30 AF XY: 0.00000987 AC XY: 6 AN XY: 608160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000100

Gnomad4 OTH exome AF: 0.0000818

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151266 Hom.: 0 Cov.: 33 AF XY: 0.0000406 AC XY: 3 AN XY: 73832

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000491

ExAC AF: 0.0000118 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4 of the COL9A3 protein (p.Pro4Leu). This variant is present in population databases (rs749401290, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with COL9A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1314108). 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 with a negative predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	12
Dann	Benign	0.91
DEOGEN2	Benign	0.0023	T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.13	N
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.75	T
Polyphen		0.0070	B;B
Vest4		0.076
MVP		0.78
MPC		0.072
ClinPred		0.34	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.10
gMVP		0.30

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: rs749401290; hg19: chr20-61448427;