chr20-62817083-T-C

Variant names:

• chr20-62817083-T-C
• rs770930161
• NM_001853.4:c.19T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001853.4(COL9A3):​c.19T>C​(p.Cys7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000323 in 1,239,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C7S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056129575).

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.19T>C	p.Cys7Arg	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.19T>C	p.Cys7Arg	missense	Exon 1 of 32	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.19T>C	p.Cys7Arg	missense	Exon 1 of 33	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.19T>C	p.Cys7Arg	missense	Exon 1 of 31	ENSP00000564791.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000323 AC: 4 AN: 1239020 Hom.: 0 Cov.: 30 AF XY: 0.00000327 AC XY: 2 AN XY: 611060

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24818

American (AMR) AF: 0.00 AC: 0 AN: 23684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20130

East Asian (EAS) AF: 0.00 AC: 0 AN: 24268

South Asian (SAS) AF: 0.00 AC: 0 AN: 65268

European-Finnish (FIN) AF: 0.0000337 AC: 1 AN: 29634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3458

European-Non Finnish (NFE) AF: 0.00000300 AC: 3 AN: 998564

Other (OTH) AF: 0.00 AC: 0 AN: 49196

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0261725), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.1
DANN	Benign	0.22
DEOGEN2	Benign	0.000061	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-1.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.18
Sift	Benign	0.40	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.40		Gain of methylation at C7 (P = 0.006)
MVP		0.33
MPC		0.13
ClinPred		0.35	T
GERP RS		0.24
PromoterAI		-0.0015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.088
gMVP		0.55
Mutation Taster		=94/6	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: rs770930161; hg19: chr20-61448435; COSMIC: COSV106406169; COSMIC: COSV106406169;