rs36094661

Variant names:

• chr20-62825772-G-A
• rs36094661
• NM_001853.4:c.631-45G>A

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.631-45G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,545,894 control chromosomes in the GnomAD database, including 19,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1348 hom., cov: 34)
  • Exomes 𝑓: 0.16 (18415 hom.)
• Consequence: COL9A3 NM_001853.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.837
• Publications: 7 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 (BayesDel_noAF=-0.84).
• BP6: Variant 20-62825772-G-A is Benign according to our data. Variant chr20-62825772-G-A is described in ClinVar as Benign. ClinVar VariationId is 258429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 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.631-45G>A		intron	N/A	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.631-45G>A		intron	N/A	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.682-45G>A		intron	N/A	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.559-45G>A		intron	N/A	ENSP00000564791.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18777 AN: 152170 Hom.: 1349 Cov.: 34

Gnomad AFR AF: 0.0569

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0987

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.0740

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.122 AC: 19065 AN: 156332 AF XY: 0.122

Gnomad AFR exome AF: 0.0602

Gnomad AMR exome AF: 0.0697

Gnomad ASJ exome AF: 0.118

Gnomad EAS exome AF: 0.0346

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.156 AC: 218046 AN: 1393606 Hom.: 18415 Cov.: 30 AF XY: 0.154 AC XY: 106229 AN XY: 687722

African (AFR) AF: 0.0533 AC: 1680 AN: 31504

American (AMR) AF: 0.0730 AC: 2606 AN: 35712

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3142 AN: 25136

East Asian (EAS) AF: 0.0290 AC: 1035 AN: 35716

South Asian (SAS) AF: 0.0727 AC: 5752 AN: 79156

European-Finnish (FIN) AF: 0.191 AC: 9207 AN: 48090

Middle Eastern (MID) AF: 0.128 AC: 727 AN: 5686

European-Non Finnish (NFE) AF: 0.173 AC: 185946 AN: 1074736

Other (OTH) AF: 0.137 AC: 7951 AN: 57870

GnomAD4 genome AF: 0.123 AC: 18773 AN: 152288 Hom.: 1348 Cov.: 34 AF XY: 0.122 AC XY: 9087 AN XY: 74456

African (AFR) AF: 0.0568 AC: 2360 AN: 41584

American (AMR) AF: 0.0987 AC: 1510 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 426 AN: 3470

East Asian (EAS) AF: 0.0361 AC: 187 AN: 5180

South Asian (SAS) AF: 0.0743 AC: 359 AN: 4832

European-Finnish (FIN) AF: 0.194 AC: 2059 AN: 10616

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.169 AC: 11467 AN: 67982

Other (OTH) AF: 0.133 AC: 282 AN: 2114

Alfa AF: 0.138 Hom.: 283

Bravo AF: 0.114

Asia WGS AF: 0.0490 AC: 172 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.77
DANN	Benign	0.85
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

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: rs36094661; hg19: chr20-61457124; COSMIC: COSV59653072; COSMIC: COSV59653072;