rs751557

Variant names:

• chr20-62832170-C-A
• rs751557
• NM_001853.4:c.1304C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-62832170-C-A
• chr20-62832170-C-G

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.1304C>A​(p.Ala435Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,605,876 control chromosomes in the GnomAD database, including 35,943 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. A435K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.24 (5433 hom., cov: 34)
  • Exomes 𝑓: 0.20 (30510 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.552
• Publications: 32 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=0.012107581).
• BP6: Variant 20-62832170-C-A is Benign according to our data. Variant chr20-62832170-C-A is described in ClinVar as Benign. ClinVar VariationId is 195873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 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.1304C>A	p.Ala435Glu	missense	Exon 25 of 32	NP_001844.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.1304C>A	p.Ala435Glu	missense	Exon 25 of 32	ENSP00000496793.1	Q14050
	COL9A3	ENST00000934236.1		c.1355C>A	p.Ala452Glu	missense	Exon 26 of 33	ENSP00000604295.1
	COL9A3	ENST00000894732.1		c.1232C>A	p.Ala411Glu	missense	Exon 24 of 31	ENSP00000564791.1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37221 AN: 152156 Hom.: 5424 Cov.: 34

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.0592

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.175 AC: 43549 AN: 249060 AF XY: 0.172

Gnomad AFR exome AF: 0.411

Gnomad AMR exome AF: 0.0981

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.0564

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.200

Gnomad OTH exome AF: 0.182

GnomAD4 exome AF: 0.195 AC: 283521 AN: 1453602 Hom.: 30510 Cov.: 33 AF XY: 0.192 AC XY: 138993 AN XY: 723428

African (AFR) AF: 0.423 AC: 14068 AN: 33240

American (AMR) AF: 0.105 AC: 4696 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 4015 AN: 26082

East Asian (EAS) AF: 0.0491 AC: 1948 AN: 39678

South Asian (SAS) AF: 0.104 AC: 8995 AN: 86118

European-Finnish (FIN) AF: 0.202 AC: 10550 AN: 52342

Middle Eastern (MID) AF: 0.192 AC: 1107 AN: 5752

European-Non Finnish (NFE) AF: 0.205 AC: 226753 AN: 1105552

Other (OTH) AF: 0.189 AC: 11389 AN: 60190

GnomAD4 genome AF: 0.245 AC: 37268 AN: 152274 Hom.: 5433 Cov.: 34 AF XY: 0.238 AC XY: 17703 AN XY: 74476

African (AFR) AF: 0.407 AC: 16891 AN: 41526

American (AMR) AF: 0.158 AC: 2424 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3468

East Asian (EAS) AF: 0.0591 AC: 307 AN: 5192

South Asian (SAS) AF: 0.107 AC: 515 AN: 4832

European-Finnish (FIN) AF: 0.205 AC: 2171 AN: 10612

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13790 AN: 68008

Other (OTH) AF: 0.222 AC: 469 AN: 2116

Alfa AF: 0.216 Hom.: 8759

Bravo AF: 0.250

TwinsUK AF: 0.221 AC: 820

ALSPAC AF: 0.208 AC: 800

ESP6500AA AF: 0.397 AC: 1747

ESP6500EA AF: 0.206 AC: 1774

ExAC AF: 0.182 AC: 22049

Asia WGS AF: 0.100 AC: 350 AN: 3478

EpiCase AF: 0.193

EpiControl AF: 0.200

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Epiphyseal dysplasia, multiple, 3 (2)
-	-	1	Connective tissue disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.00099	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.64	N
PhyloP100		0.55
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.23
Sift	Benign	0.37	T
Sift4G	Benign	0.58	T
Polyphen		0.081	B
Vest4		0.11
MPC		0.40
ClinPred		0.013	T
GERP RS		4.2
Varity_R		0.091
gMVP		0.62
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.070		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: rs751557; hg19: chr20-61463522; COSMIC: COSV59653980; COSMIC: COSV59653980;