20-62817071-G-C

Variant names:

• chr20-62817071-G-C
• rs780941765
• NM_001853.4:c.7G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001853.4(COL9A3):​c.7G>C​(p.Gly3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,378,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.21
• 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Stickler syndrome

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.084466845).

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.7G>C	p.Gly3Arg	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.7G>C	p.Gly3Arg	missense	Exon 1 of 32	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.7G>C	p.Gly3Arg	missense	Exon 1 of 33	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.7G>C	p.Gly3Arg	missense	Exon 1 of 31	ENSP00000564791.1

Frequencies

GnomAD3 genomes AF: 0.0000397 AC: 6 AN: 151192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 26 AN: 1227376 Hom.: 0 Cov.: 29 AF XY: 0.0000182 AC XY: 11 AN XY: 604846

African (AFR) AF: 0.0000407 AC: 1 AN: 24540

American (AMR) AF: 0.00 AC: 0 AN: 22820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19748

East Asian (EAS) AF: 0.00 AC: 0 AN: 23858

South Asian (SAS) AF: 0.0000157 AC: 1 AN: 63518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3402

European-Non Finnish (NFE) AF: 0.0000212 AC: 21 AN: 991868

Other (OTH) AF: 0.0000618 AC: 3 AN: 48544

GnomAD4 genome AF: 0.0000463 AC: 7 AN: 151298 Hom.: 0 Cov.: 33 AF XY: 0.0000676 AC XY: 5 AN XY: 73926

African (AFR) AF: 0.0000966 AC: 4 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67710

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions as Germline

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	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	5.5
DANN	Benign	0.97
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.28	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-1.2
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.29
Sift	Benign	0.79	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.0	B
Vest4		0.12
MutPred		0.47		Gain of methylation at G3 (P = 0.0115)
MVP		0.55
MPC		0.083
ClinPred		0.11	T
GERP RS		-1.6
PromoterAI		-0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.11
gMVP		0.42
Mutation Taster		=96/4	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: rs780941765; hg19: chr20-61448423;