rs45476191

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001853.4(COL9A3):​c.520-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0135 in 1,599,674 control chromosomes in the GnomAD database, including 212 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0090 ( 12 hom., cov: 33)
Exomes 𝑓: 0.014 ( 200 hom. )

Consequence

COL9A3
NM_001853.4 splice_region, intron

Scores

2
Splicing: ADA: 0.0003695
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.647
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.62).
BP6
Variant 20-62824439-C-T is Benign according to our data. Variant chr20-62824439-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62824439-C-T is described in Lovd as [Likely_benign]. Variant chr20-62824439-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00905 (1378/152272) while in subpopulation SAS AF= 0.0263 (127/4828). AF 95% confidence interval is 0.0226. There are 12 homozygotes in gnomad4. There are 620 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL9A3NM_001853.4 linkc.520-6C>T splice_region_variant, intron_variant Intron 10 of 31 ENST00000649368.1 NP_001844.3 Q14050

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL9A3ENST00000649368.1 linkc.520-6C>T splice_region_variant, intron_variant Intron 10 of 31 NM_001853.4 ENSP00000496793.1 Q14050

Frequencies

GnomAD3 genomes
AF:
0.00906
AC:
1379
AN:
152154
Hom.:
12
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00249
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00301
Gnomad ASJ
AF:
0.00432
Gnomad EAS
AF:
0.0226
Gnomad SAS
AF:
0.0265
Gnomad FIN
AF:
0.00226
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.0137
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.0111
AC:
2512
AN:
225928
Hom.:
25
AF XY:
0.0123
AC XY:
1512
AN XY:
122546
show subpopulations
Gnomad AFR exome
AF:
0.00115
Gnomad AMR exome
AF:
0.00279
Gnomad ASJ exome
AF:
0.00188
Gnomad EAS exome
AF:
0.0206
Gnomad SAS exome
AF:
0.0252
Gnomad FIN exome
AF:
0.00191
Gnomad NFE exome
AF:
0.0125
Gnomad OTH exome
AF:
0.00588
GnomAD4 exome
AF:
0.0139
AC:
20138
AN:
1447402
Hom.:
200
Cov.:
32
AF XY:
0.0143
AC XY:
10271
AN XY:
718848
show subpopulations
Gnomad4 AFR exome
AF:
0.00180
Gnomad4 AMR exome
AF:
0.00283
Gnomad4 ASJ exome
AF:
0.00286
Gnomad4 EAS exome
AF:
0.0188
Gnomad4 SAS exome
AF:
0.0253
Gnomad4 FIN exome
AF:
0.00301
Gnomad4 NFE exome
AF:
0.0146
Gnomad4 OTH exome
AF:
0.0110
GnomAD4 genome
AF:
0.00905
AC:
1378
AN:
152272
Hom.:
12
Cov.:
33
AF XY:
0.00833
AC XY:
620
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.00248
Gnomad4 AMR
AF:
0.00301
Gnomad4 ASJ
AF:
0.00432
Gnomad4 EAS
AF:
0.0228
Gnomad4 SAS
AF:
0.0263
Gnomad4 FIN
AF:
0.00226
Gnomad4 NFE
AF:
0.0137
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.0105
Hom.:
10
Bravo
AF:
0.00815
Asia WGS
AF:
0.0250
AC:
88
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 30, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

not specified Benign:3
-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 06, 2020
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Intervertebral disc disorder;C1832998:Epiphyseal dysplasia, multiple, 3 Benign:1
Aug 12, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Connective tissue disorder Benign:1
Mar 11, 2022
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.62
CADD
Benign
11
DANN
Benign
0.93
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00037
dbscSNV1_RF
Benign
0.022
SpliceAI score (max)
0.19
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs45476191; hg19: chr20-61455791; API