20-62836212-C-T

Position:

• chr20-62836212-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001853.4(COL9A3):​c.1427C>T​(p.Pro476Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,192 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P476R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.81

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A3	NM_001853.4	c.1427C>T	p.Pro476Leu	missense_variant	28/32	ENST00000649368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A3	ENST00000649368.1	c.1427C>T	p.Pro476Leu	missense_variant	28/32		NM_001853.4	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248964 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135256

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461192 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726924

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.84	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
Polyphen		1.0	D;D
Vest4		0.55
MutPred		0.35		Loss of phosphorylation at T479 (P = 0.0713);Loss of phosphorylation at T479 (P = 0.0713);
MVP		0.93
MPC		0.13
ClinPred		0.53	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.65

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: rs142066316; hg19: chr20-61467564;