20-62817083-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001853.4(COL9A3):c.19T>A(p.Cys7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,390,164 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. C7C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (2 hom.)
• Consequence: COL9A3 NM_001853.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.07

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046109855).
• BP6: Variant 20-62817083-T-A is Benign according to our data. Variant chr20-62817083-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 426860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62817083-T-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00114 (173/151138) while in subpopulation AFR AF= 0.00385 (159/41352). AF 95% confidence interval is 0.00336. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A3	NM_001853.4	c.19T>A	p.Cys7Ser	missense_variant	1/32	ENST00000649368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A3	ENST00000649368.1	c.19T>A	p.Cys7Ser	missense_variant	1/32		NM_001853.4	P1
COL9A3	ENST00000477612.5	n.75-484T>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 172 AN: 151032 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00383

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000725

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000115 AC: 9 AN: 78486 Hom.: 0 AF XY: 0.000110 AC XY: 5 AN XY: 45544

Gnomad AFR exome AF: 0.00253

Gnomad AMR exome AF: 0.000415

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 147 AN: 1239026 Hom.: 2 Cov.: 30 AF XY: 0.000108 AC XY: 66 AN XY: 611062

Gnomad4 AFR exome AF: 0.00455

Gnomad4 AMR exome AF: 0.000296

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000153

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000300

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.00114 AC: 173 AN: 151138 Hom.: 0 Cov.: 33 AF XY: 0.00100 AC XY: 74 AN XY: 73850

Gnomad4 AFR AF: 0.00385

Gnomad4 AMR AF: 0.000724

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000296

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.00107 Hom.: 0

ExAC AF: 0.000116 AC: 10

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2019	Has not been previously published as pathogenic or benign to our knowledge -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	- -

COL9A3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	4.1
Dann	Benign	0.47
DEOGEN2	Benign	0.000061	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.049	N
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	-0.60	N;N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.81	D
Polyphen		0.0	B;B
Vest4		0.087
MutPred		0.31		Gain of phosphorylation at C7 (P = 0.035);Gain of phosphorylation at C7 (P = 0.035);
MVP		0.39
MPC		0.086
ClinPred		0.0023	T
GERP RS		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.034
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs770930161; hg19: chr20-61448435;