NM_001853.4:c.887C>T

Variant names:

• chr20-62827963-C-T
• rs45628843
• NM_001853.4:c.887C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001853.4(COL9A3):​c.887C>T​(p.Pro296Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 1,612,860 control chromosomes in the GnomAD database, including 2,435 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P296P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.040 (197 hom., cov: 33)
  • Exomes 𝑓: 0.052 (2238 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.220
• Publications: 9 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029235482).
• BP6: Variant 20-62827963-C-T is Benign according to our data. Variant chr20-62827963-C-T is described in ClinVar as Benign. ClinVar VariationId is 258436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

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.887C>T	p.Pro296Leu	missense	Exon 17 of 32	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.887C>T	p.Pro296Leu	missense	Exon 17 of 32	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.938C>T	p.Pro313Leu	missense	Exon 18 of 33	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.815C>T	p.Pro272Leu	missense	Exon 16 of 31	ENSP00000564791.1

Frequencies

GnomAD3 genomes AF: 0.0399 AC: 6075 AN: 152152 Hom.: 197 Cov.: 33

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0445

Gnomad ASJ AF: 0.0380

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0612

Gnomad OTH AF: 0.0464

GnomAD2 exomes AF: 0.0387 AC: 9686 AN: 250168 AF XY: 0.0388

Gnomad AFR exome AF: 0.00993

Gnomad AMR exome AF: 0.0352

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0373

Gnomad NFE exome AF: 0.0585

Gnomad OTH exome AF: 0.0501

GnomAD4 exome AF: 0.0517 AC: 75547 AN: 1460590 Hom.: 2238 Cov.: 32 AF XY: 0.0507 AC XY: 36852 AN XY: 726612

African (AFR) AF: 0.00968 AC: 324 AN: 33478

American (AMR) AF: 0.0364 AC: 1628 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0402 AC: 1050 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00720 AC: 621 AN: 86258

European-Finnish (FIN) AF: 0.0363 AC: 1899 AN: 52274

Middle Eastern (MID) AF: 0.0359 AC: 207 AN: 5768

European-Non Finnish (NFE) AF: 0.0603 AC: 67076 AN: 1111888

Other (OTH) AF: 0.0454 AC: 2739 AN: 60374

GnomAD4 genome AF: 0.0399 AC: 6071 AN: 152270 Hom.: 197 Cov.: 33 AF XY: 0.0382 AC XY: 2842 AN XY: 74448

African (AFR) AF: 0.0119 AC: 495 AN: 41548

American (AMR) AF: 0.0444 AC: 679 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 132 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4828

European-Finnish (FIN) AF: 0.0364 AC: 386 AN: 10612

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0612 AC: 4159 AN: 68012

Other (OTH) AF: 0.0459 AC: 97 AN: 2114

Alfa AF: 0.0493 Hom.: 392

Bravo AF: 0.0398

TwinsUK AF: 0.0634 AC: 235

ALSPAC AF: 0.0589 AC: 227

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.0613 AC: 527

ExAC AF: 0.0377 AC: 4569

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0559

EpiControl AF: 0.0643

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.9
DANN	Benign	0.60
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.70	N
PhyloP100		-0.22
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.25
Sift	Benign	0.63	T
Sift4G	Uncertain	0.050	T
Polyphen		0.027	B
Vest4		0.062
MPC		0.079
ClinPred		0.016	T
GERP RS		1.1
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.11
gMVP		0.56
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45628843; hg19: chr20-61459315;