20-62827195-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001853.4(COL9A3):c.793-46A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 1,605,714 control chromosomes in the GnomAD database, including 192,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.56 ( 25897 hom., cov: 32)

Exomes 𝑓: 0.47 ( 166447 hom. )

Consequence

COL9A3
NM_001853.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.84

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

epiphyseal dysplasia, multiple, 3
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
Stickler syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, ClinGen
Stickler syndrome, type 6
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
multiple epiphyseal dysplasia due to collagen 9 anomaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive Stickler syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

COL9A3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP6

Variant 20-62827195-A-T is Benign according to our data. Variant chr20-62827195-A-T is described in ClinVar as Benign. ClinVar VariationId is 258434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.789 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A3	NM_001853.4 link	c.793-46A>T		intron_variant	Intron 15 of 31	ENST00000649368.1	NP_001844.3	Q14050

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A3	ENST00000649368.1 link	c.793-46A>T		intron_variant	Intron 15 of 31		NM_001853.4	ENSP00000496793.1		Q14050
COL9A3	ENST00000463487.2 link	n.501-46A>T		intron_variant	Intron 7 of 10	5

Frequencies

GnomAD3 genomes

AF:

0.562

AC:

85226

AN:

151740

Hom.:

25833

Cov.:

show subpopulations

Gnomad AFR

AF:

0.796

Gnomad AMI

AF:

0.307

Gnomad AMR

AF:

0.514

Gnomad ASJ

AF:

0.467

Gnomad EAS

AF:

0.757

Gnomad SAS

AF:

0.549

Gnomad FIN

AF:

0.469

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.439

Gnomad OTH

AF:

0.545

GnomAD2 exomes

AF:

0.518

AC:

128969

AN:

248812

AF XY:

0.509

show subpopulations

Gnomad AFR exome

AF:

0.805

Gnomad AMR exome

AF:

0.543

Gnomad ASJ exome

AF:

0.447

Gnomad EAS exome

AF:

0.761

Gnomad FIN exome

AF:

0.472

Gnomad NFE exome

AF:

0.442

Gnomad OTH exome

AF:

0.487

GnomAD4 exome

AF:

0.471

AC:

685381

AN:

1453856

Hom.:

166447

Cov.:

AF XY:

0.472

AC XY:

341501

AN XY:

723732

show subpopulations

African (AFR)

AF:

0.813

AC:

27124

AN:

33352

American (AMR)

AF:

0.541

AC:

24151

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.452

AC:

11800

AN:

26094

East Asian (EAS)

AF:

0.750

AC:

29755

AN:

39658

South Asian (SAS)

AF:

0.535

AC:

46025

AN:

86092

European-Finnish (FIN)

AF:

0.463

AC:

24170

AN:

52150

Middle Eastern (MID)

AF:

0.550

AC:

3084

AN:

5612

European-Non Finnish (NFE)

AF:

0.442

AC:

489301

AN:

1106128

Other (OTH)

AF:

0.499

AC:

29971

AN:

60112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

18143

36286

54430

72573

90716

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15046

30092

45138

60184

75230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.562

AC:

85351

AN:

151858

Hom.:

25897

Cov.:

AF XY:

0.561

AC XY:

41624

AN XY:

74198

show subpopulations

African (AFR)

AF:

0.796

AC:

33035

AN:

41490

American (AMR)

AF:

0.514

AC:

7840

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.467

AC:

1617

AN:

3466

East Asian (EAS)

AF:

0.757

AC:

3880

AN:

5124

South Asian (SAS)

AF:

0.549

AC:

2640

AN:

4806

European-Finnish (FIN)

AF:

0.469

AC:

4946

AN:

10556

Middle Eastern (MID)

AF:

0.537

AC:

158

AN:

294

European-Non Finnish (NFE)

AF:

0.439

AC:

29795

AN:

67844

Other (OTH)

AF:

0.551

AC:

1161

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1781

3563

5344

7126

8907

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

710

1420

2130

2840

3550

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.485

Hom.:

3342

Bravo

AF:

0.577

Asia WGS

AF:

0.657

AC:

2284

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.94

CADD

Benign

0.12

(source)

DANN

Benign

0.50

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over