rs147947060

Positions:

chr20-62821797-T-C

Variant summary

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

The NM_001853.4(COL9A3):c.410T>C(p.Leu137Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,605,626 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. L137F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 28 hom. )

Consequence

COL9A3
NM_001853.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.79

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]

COL9A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009360015).

BP6

Variant 20-62821797-T-C is Benign according to our data. Variant chr20-62821797-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 258424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-62821797-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0039 (593/152218) while in subpopulation SAS AF= 0.00518 (25/4824). AF 95% confidence interval is 0.00418. There are 4 homozygotes in gnomad4. There are 272 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A3	NM_001853.4 linkuse as main transcript	c.410T>C	p.Leu137Pro	missense_variant	8/32	ENST00000649368.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
COL9A3	ENST00000649368.1 linkuse as main transcript	c.410T>C	p.Leu137Pro	missense_variant	8/32		NM_001853.4	P1
COL9A3	ENST00000452372.2 linkuse as main transcript	c.299T>C	p.Leu100Pro	missense_variant	7/12	5
COL9A3	ENST00000477612.5 linkuse as main transcript	n.406T>C		non_coding_transcript_exon_variant	8/12	3
COL9A3	ENST00000489045.5 linkuse as main transcript	n.456T>C		non_coding_transcript_exon_variant	7/14	5

Frequencies

GnomAD3 genomes

AF:

0.00391

AC:

594

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00360

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00462

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00386

AC:

934

AN:

241728

Hom.:

AF XY:

0.00404

AC XY:

534

AN XY:

132060

show subpopulations

Gnomad AFR exome

AF:

0.00386

Gnomad AMR exome

AF:

0.00187

Gnomad ASJ exome

AF:

0.0167

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00547

Gnomad FIN exome

AF:

0.000435

Gnomad NFE exome

AF:

0.00407

Gnomad OTH exome

AF:

0.00614

GnomAD4 exome

AF:

0.00397

AC:

5771

AN:

1453408

Hom.:

Cov.:

AF XY:

0.00401

AC XY:

2900

AN XY:

722990

show subpopulations

Gnomad4 AFR exome

AF:

0.00300

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.0170

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00565

Gnomad4 FIN exome

AF:

0.000695

Gnomad4 NFE exome

AF:

0.00392

Gnomad4 OTH exome

AF:

0.00415

GnomAD4 genome

AF:

0.00390

AC:

593

AN:

152218

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

272

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00359

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.0210

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00460

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00485

Hom.:

Bravo

AF:

0.00393

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00315

AC:

ExAC

AF:

0.00382

AC:

461

Asia WGS

AF:

0.00260

AC:

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:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	COL9A3: BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 22, 2015	- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.00037

T;T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.68

.;T;T

M_CAP

Benign

0.067

MetaRNN

Benign

0.0094

T;T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

-1.2

N;N;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.10

.;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.13

.;T;T

Sift4G

Benign

0.41

.;T;T

Polyphen

0.0050

B;B;.

Vest4

0.38

MVP

0.75

MPC

0.11

ClinPred

0.0086

GERP RS

4.8

Varity_R

0.13

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over