rs79269394

Variant names:

• chr20-62833023-A-G
• rs79269394
• NM_001853.4:c.1327A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001853.4(COL9A3):​c.1327A>G​(p.Ile443Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,613,604 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (27 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (16 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.26
• Publications: 5 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=0.0038558543).
• BP6: Variant 20-62833023-A-G is Benign according to our data. Variant chr20-62833023-A-G is described in ClinVar as Benign. ClinVar VariationId is 258405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00951 (1449/152298) while in subpopulation AFR AF = 0.0309 (1283/41550). AF 95% confidence interval is 0.0295. There are 27 homozygotes in GnomAd4. There are 689 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR,AD gene

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.1327A>G	p.Ile443Val	missense	Exon 26 of 32	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.1327A>G	p.Ile443Val	missense	Exon 26 of 32	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.1378A>G	p.Ile460Val	missense	Exon 27 of 33	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.1255A>G	p.Ile419Val	missense	Exon 25 of 31	ENSP00000564791.1

Frequencies

GnomAD3 genomes AF: 0.00949 AC: 1444 AN: 152180 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00262 AC: 659 AN: 251102 AF XY: 0.00213

Gnomad AFR exome AF: 0.0320

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00111 AC: 1620 AN: 1461306 Hom.: 16 Cov.: 30 AF XY: 0.00101 AC XY: 736 AN XY: 726988

African (AFR) AF: 0.0291 AC: 973 AN: 33444

American (AMR) AF: 0.00309 AC: 138 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86248

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53328

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.000273 AC: 303 AN: 1111630

Other (OTH) AF: 0.00287 AC: 173 AN: 60356

GnomAD4 genome AF: 0.00951 AC: 1449 AN: 152298 Hom.: 27 Cov.: 33 AF XY: 0.00925 AC XY: 689 AN XY: 74470

African (AFR) AF: 0.0309 AC: 1283 AN: 41550

American (AMR) AF: 0.00765 AC: 117 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68028

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00458 Hom.: 15

Bravo AF: 0.0111

ESP6500AA AF: 0.0304 AC: 134

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00334 AC: 405

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.61
DANN	Benign	0.69
DEOGEN2	Benign	0.00043	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.48	N
PhyloP100		1.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.21
Sift	Benign	0.80	T
Sift4G	Benign	0.32	T
Polyphen		0.0050	B
Vest4		0.23
MVP		0.55
MPC		0.086
ClinPred		0.00088	T
GERP RS		-1.8
Varity_R		0.026
gMVP		0.69
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs79269394; hg19: chr20-61464375;