rs890399221

Variant names:

• chr20-62817077-C-A
• rs890399221
• NM_001853.4:c.13C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-62817077-C-A
• chr20-62817077-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001853.4(COL9A3):​c.13C>A​(p.Arg5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R5C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., 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: 0.470
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• epiphyseal dysplasia, multiple, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Stickler syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Ambry Genetics, Genomics England PanelApp
• Stickler syndrome, type 6

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• multiple epiphyseal dysplasia due to collagen 9 anomaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16604939).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001853.4. 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
	COL9A3	NM_001853.4	MANE Select	c.13C>A	p.Arg5Ser	missense	Exon 1 of 32	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.13C>A	p.Arg5Ser	missense	Exon 1 of 32	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.13C>A	p.Arg5Ser	missense	Exon 1 of 33	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.13C>A	p.Arg5Ser	missense	Exon 1 of 31	ENSP00000564791.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1235142 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 608938

African (AFR) AF: 0.00 AC: 0 AN: 24708

American (AMR) AF: 0.00 AC: 0 AN: 23428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20006

East Asian (EAS) AF: 0.00 AC: 0 AN: 24148

South Asian (SAS) AF: 0.00 AC: 0 AN: 64660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3446

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 996322

Other (OTH) AF: 0.00 AC: 0 AN: 48990

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151394 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73976

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67722

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	11
DANN	Benign	0.75
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.27	T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.47
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.33		Loss of methylation at R5 (P = 0.0126)
MVP		0.67
MPC		0.079
ClinPred		0.27	T
GERP RS		2.4
PromoterAI		0.0020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.18
gMVP		0.40
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs890399221; hg19: chr20-61448429;