chr20-62838713-G-A

Variant names:

• chr20-62838713-G-A
• rs142792529
• NM_001853.4:c.1816G>A

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.1816G>A​(p.Ala606Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,552,770 control chromosomes in the GnomAD database, including 148 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A606S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0090 (5 hom., cov: 32)
  • Exomes 𝑓: 0.012 (143 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.836
• Publications: 8 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: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
• Stickler syndrome

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

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=0.0031912327).
• BP6: Variant 20-62838713-G-A is Benign according to our data. Variant chr20-62838713-G-A is described in ClinVar as Benign. ClinVar VariationId is 258418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00898 (1367/152300) while in subpopulation NFE AF = 0.0141 (959/68028). AF 95% confidence interval is 0.0134. There are 5 homozygotes in GnomAd4. There are 661 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR 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.1816G>A	p.Ala606Thr	missense	Exon 31 of 32	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.1816G>A	p.Ala606Thr	missense	Exon 31 of 32	ENSP00000496793.1
	COL9A3	ENST00000467819.5	TSL:1	n.327G>A		non_coding_transcript_exon	Exon 3 of 4
	COL9A3	ENST00000934236.1		c.1867G>A	p.Ala623Thr	missense	Exon 32 of 33	ENSP00000604295.1

Frequencies

GnomAD3 genomes AF: 0.00900 AC: 1370 AN: 152182 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00829

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00869 AC: 1374 AN: 158024 AF XY: 0.00892

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00515

Gnomad EAS exome AF: 0.000348

Gnomad FIN exome AF: 0.0168

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.0125 AC: 17451 AN: 1400470 Hom.: 143 Cov.: 32 AF XY: 0.0123 AC XY: 8476 AN XY: 690850

African (AFR) AF: 0.00190 AC: 60 AN: 31652

American (AMR) AF: 0.00265 AC: 95 AN: 35822

Ashkenazi Jewish (ASJ) AF: 0.00445 AC: 112 AN: 25188

East Asian (EAS) AF: 0.000390 AC: 14 AN: 35874

South Asian (SAS) AF: 0.00816 AC: 647 AN: 79272

European-Finnish (FIN) AF: 0.0169 AC: 835 AN: 49358

Middle Eastern (MID) AF: 0.00527 AC: 30 AN: 5698

European-Non Finnish (NFE) AF: 0.0140 AC: 15118 AN: 1079532

Other (OTH) AF: 0.00930 AC: 540 AN: 58074

GnomAD4 genome AF: 0.00898 AC: 1367 AN: 152300 Hom.: 5 Cov.: 32 AF XY: 0.00888 AC XY: 661 AN XY: 74476

African (AFR) AF: 0.00262 AC: 109 AN: 41556

American (AMR) AF: 0.00346 AC: 53 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.00809 AC: 39 AN: 4820

European-Finnish (FIN) AF: 0.0169 AC: 179 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0141 AC: 959 AN: 68028

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

Alfa AF: 0.0114 Hom.: 38

Bravo AF: 0.00754

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00374 AC: 16

ESP6500EA AF: 0.0123 AC: 103

ExAC AF: 0.00533 AC: 526

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	not specified (2)
-	-	1	Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	3.2
DANN	Benign	0.79
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.84
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.18
Sift	Benign	0.57	T
Sift4G	Benign	0.53	T
Polyphen		0.20	B
Vest4		0.21
MVP		0.53
MPC		0.30
ClinPred		0.0057	T
GERP RS		-0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.35
Mutation Taster		=98/2	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: rs142792529; hg19: chr20-61470065; COSMIC: COSV99071334; COSMIC: COSV99071334;