chr20-62832149-T-C

Variant names:

• chr20-62832149-T-C
• rs741758
• NM_001853.4:c.1288-5T>C

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.1288-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 1,603,270 control chromosomes in the GnomAD database, including 105,074 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11040 hom., cov: 34)
  • Exomes 𝑓: 0.35 (94034 hom.)
• Consequence: COL9A3 NM_001853.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002446
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0390
• Publications: 21 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 (BayesDel_noAF=-0.91).
• BP6: Variant 20-62832149-T-C is Benign according to our data. Variant chr20-62832149-T-C is described in ClinVar as Benign. ClinVar VariationId is 195872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	NM_001853.4	MANE Select	c.1288-5T>C		splice_region intron	N/A	NP_001844.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A3	ENST00000649368.1	MANE Select	c.1288-5T>C		splice_region intron	N/A	ENSP00000496793.1
	COL9A3	ENST00000466192.5	TSL:2	n.1010T>C		non_coding_transcript_exon	Exon 1 of 8
	COL9A3	ENST00000469852.5	TSL:3	n.579T>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56619 AN: 152082 Hom.: 11030 Cov.: 34

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.284

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.345

GnomAD2 exomes AF: 0.324 AC: 80834 AN: 249362 AF XY: 0.322

Gnomad AFR exome AF: 0.467

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.162

Gnomad FIN exome AF: 0.387

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.354 AC: 513087 AN: 1451070 Hom.: 94034 Cov.: 33 AF XY: 0.351 AC XY: 253483 AN XY: 722262

African (AFR) AF: 0.484 AC: 16043 AN: 33156

American (AMR) AF: 0.242 AC: 10816 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 7764 AN: 26098

East Asian (EAS) AF: 0.150 AC: 5934 AN: 39680

South Asian (SAS) AF: 0.274 AC: 23564 AN: 86102

European-Finnish (FIN) AF: 0.381 AC: 19952 AN: 52424

Middle Eastern (MID) AF: 0.341 AC: 1964 AN: 5754

European-Non Finnish (NFE) AF: 0.368 AC: 406263 AN: 1103112

Other (OTH) AF: 0.346 AC: 20787 AN: 60072

GnomAD4 genome AF: 0.372 AC: 56672 AN: 152200 Hom.: 11040 Cov.: 34 AF XY: 0.367 AC XY: 27313 AN XY: 74406

African (AFR) AF: 0.468 AC: 19449 AN: 41520

American (AMR) AF: 0.284 AC: 4340 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1063 AN: 3468

East Asian (EAS) AF: 0.151 AC: 783 AN: 5182

South Asian (SAS) AF: 0.273 AC: 1319 AN: 4828

European-Finnish (FIN) AF: 0.382 AC: 4047 AN: 10590

Middle Eastern (MID) AF: 0.373 AC: 109 AN: 292

European-Non Finnish (NFE) AF: 0.362 AC: 24611 AN: 67990

Other (OTH) AF: 0.345 AC: 731 AN: 2116

Alfa AF: 0.360 Hom.: 19112

Bravo AF: 0.370

Asia WGS AF: 0.258 AC: 897 AN: 3478

EpiCase AF: 0.351

EpiControl AF: 0.345

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Epiphyseal dysplasia, multiple, 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.4
DANN	Benign	0.58
PhyloP100		0.039
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.13		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: rs741758; hg19: chr20-61463501; COSMIC: COSV59650443; COSMIC: COSV59650443;