rs140330666

chr20-62826819-C-T

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.791C>T(p.Ala264Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,612,778 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A264T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: COL9A3 NM_001853.4 missense, splice_region
• Scores: Splicing: ADA: 0.0003479
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.658

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=0.012078643).
• BP6: Variant 20-62826819-C-T is Benign according to our data. Variant chr20-62826819-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 376885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62826819-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00149 (227/152292) while in subpopulation AFR AF= 0.00493 (205/41562). AF 95% confidence interval is 0.00438. There are 1 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A3	NM_001853.4	c.791C>T	p.Ala264Val	missense_variant, splice_region_variant	15/32	ENST00000649368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A3	ENST00000649368.1	c.791C>T	p.Ala264Val	missense_variant, splice_region_variant	15/32		NM_001853.4	P1
COL9A3	ENST00000463487.2	n.499C>T		splice_region_variant, non_coding_transcript_exon_variant	7/11	5
COL9A3	ENST00000489045.5	n.837C>T		non_coding_transcript_exon_variant	14/14	5

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152174 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00495

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000430 AC: 107 AN: 248984 Hom.: 0 AF XY: 0.000333 AC XY: 45 AN XY: 135190

Gnomad AFR exome AF: 0.00568

Gnomad AMR exome AF: 0.000319

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: 0.0000356

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1460486 Hom.: 1 Cov.: 32 AF XY: 0.000140 AC XY: 102 AN XY: 726556

Gnomad4 AFR exome AF: 0.00484

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152292 Hom.: 1 Cov.: 33 AF XY: 0.00146 AC XY: 109 AN XY: 74458

Gnomad4 AFR AF: 0.00493

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000412 Hom.: 0

Bravo AF: 0.00165

ESP6500AA AF: 0.00478 AC: 21

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000471 AC: 57

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

COL9A3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

This variant is classified as 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	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	13
Dann	Benign	0.90
DEOGEN2	Benign	0.0017	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.51	T
Polyphen		0.0010	B;B
Vest4		0.12
MVP		0.67
MPC		0.070
ClinPred		0.0024	T
GERP RS		-4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.048
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: rs140330666; hg19: chr20-61458171;