rs74830351

chr20-62840573-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001853.4(COL9A3):c.1896C>T(p.Asp632=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,612,582 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (9 hom., cov: 33)
  • Exomes 𝑓: 0.013 (162 hom.)
• Consequence: COL9A3 NM_001853.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.91

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 20-62840573-C-T is Benign according to our data. Variant chr20-62840573-C-T is described in ClinVar as [Benign]. Clinvar id is 258419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62840573-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.91 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00774 (1179/152342) while in subpopulation NFE AF= 0.0138 (941/68030). AF 95% confidence interval is 0.0131. There are 9 homozygotes in gnomad4. There are 536 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A3	NM_001853.4	c.1896C>T	p.Asp632=	synonymous_variant	32/32	ENST00000649368.1
COL9A3	XM_047439893.1	c.2073C>T	p.Asp691=	synonymous_variant	31/31
COL9A3	XM_047439894.1	c.1335C>T	p.Asp445=	synonymous_variant	32/32

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A3	ENST00000649368.1	c.1896C>T	p.Asp632=	synonymous_variant	32/32		NM_001853.4	P1

Frequencies

GnomAD3 genomes AF: 0.00775 AC: 1179 AN: 152224 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00690 AC: 1720 AN: 249354 Hom.: 13 AF XY: 0.00663 AC XY: 897 AN XY: 135328

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.000491

Gnomad SAS exome AF: 0.00209

Gnomad FIN exome AF: 0.00227

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.00722

GnomAD4 exome AF: 0.0131 AC: 19061 AN: 1460240 Hom.: 162 Cov.: 31 AF XY: 0.0127 AC XY: 9208 AN XY: 726484

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00229

Gnomad4 FIN exome AF: 0.00300

Gnomad4 NFE exome AF: 0.0161

Gnomad4 OTH exome AF: 0.00934

GnomAD4 genome AF: 0.00774 AC: 1179 AN: 152342 Hom.: 9 Cov.: 33 AF XY: 0.00719 AC XY: 536 AN XY: 74500

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.00529

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.0138

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0113 Hom.: 3

Bravo AF: 0.00764

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0137

EpiControl AF: 0.0105

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	COL9A3: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.13
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs74830351; hg19: chr20-61471925; COSMIC: COSV53897374; COSMIC: COSV53897374;