rs633762

Variant names:

• chr6-70255422-A-C
• rs633762
• NM_001851.6:c.1504-32T>G

Your query was ambiguous. Multiple possible variants found:

• chr6-70255422-A-C
• chr6-70255422-A-G
• chr6-70255422-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001851.6(COL9A1):​c.1504-32T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.79 in 1,596,956 control chromosomes in the GnomAD database, including 501,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (54117 hom., cov: 32)
  • Exomes 𝑓: 0.79 (447171 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.130
• Publications: 9 publications found

Genes affected

COL9A1 (HGNC:2217): (collagen type IX alpha 1 chain) This gene encodes one of the three alpha chains of type IX collagen, which is a minor (5-20%) collagen component of hyaline cartilage. Type IX collagen is usually found in tissues containing type II collagen, a fibrillar collagen. Studies in knockout mice have shown that synthesis of the alpha 1 chain is essential for assembly of type IX collagen molecules, a heterotrimeric molecule, and that lack of type IX collagen is associated with early onset osteoarthritis. Mutations in this gene are associated with osteoarthritis in humans, with multiple epiphyseal dysplasia, 6, a form of chondrodysplasia, and with Stickler syndrome, a disease characterized by ophthalmic, orofacial, articular, and auditory defects. Two transcript variants that encode different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

COL9A1 Gene-Disease associations (from GenCC):

• epiphyseal dysplasia, multiple, 6

  Inheritance: AD, AR, Unknown Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Stickler syndrome, type 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Genomics England PanelApp, PanelApp Australia, 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
• Stickler syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 6-70255422-A-C is Benign according to our data. Variant chr6-70255422-A-C is described in ClinVar as Benign. ClinVar VariationId is 258344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.1504-32T>G		intron_variant	Intron 21 of 37	ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.1504-32T>G		intron_variant	Intron 21 of 37	1	NM_001851.6	ENSP00000349790.6

Frequencies

GnomAD3 genomes AF: 0.838 AC: 127544 AN: 152130 Hom.: 54044 Cov.: 32

Gnomad AFR AF: 0.959

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.849

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.930

Gnomad SAS AF: 0.768

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.811

GnomAD2 exomes AF: 0.810 AC: 202980 AN: 250650 AF XY: 0.800

Gnomad AFR exome AF: 0.967

Gnomad AMR exome AF: 0.881

Gnomad ASJ exome AF: 0.831

Gnomad EAS exome AF: 0.921

Gnomad FIN exome AF: 0.747

Gnomad NFE exome AF: 0.773

Gnomad OTH exome AF: 0.797

GnomAD4 exome AF: 0.785 AC: 1134633 AN: 1444708 Hom.: 447171 Cov.: 28 AF XY: 0.783 AC XY: 563613 AN XY: 719836

African (AFR) AF: 0.967 AC: 32007 AN: 33116

American (AMR) AF: 0.876 AC: 39157 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 21441 AN: 26024

East Asian (EAS) AF: 0.939 AC: 37206 AN: 39628

South Asian (SAS) AF: 0.754 AC: 64710 AN: 85860

European-Finnish (FIN) AF: 0.748 AC: 39821 AN: 53246

Middle Eastern (MID) AF: 0.812 AC: 4608 AN: 5676

European-Non Finnish (NFE) AF: 0.773 AC: 847862 AN: 1096614

Other (OTH) AF: 0.799 AC: 47821 AN: 59844

GnomAD4 genome AF: 0.839 AC: 127677 AN: 152248 Hom.: 54117 Cov.: 32 AF XY: 0.837 AC XY: 62302 AN XY: 74430

African (AFR) AF: 0.959 AC: 39840 AN: 41558

American (AMR) AF: 0.849 AC: 12987 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.827 AC: 2872 AN: 3472

East Asian (EAS) AF: 0.930 AC: 4815 AN: 5178

South Asian (SAS) AF: 0.769 AC: 3703 AN: 4816

European-Finnish (FIN) AF: 0.752 AC: 7974 AN: 10610

Middle Eastern (MID) AF: 0.806 AC: 237 AN: 294

European-Non Finnish (NFE) AF: 0.777 AC: 52837 AN: 68002

Other (OTH) AF: 0.814 AC: 1721 AN: 2114

Alfa AF: 0.787 Hom.: 26337

Bravo AF: 0.852

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epiphyseal dysplasia, multiple, 6 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 23, 2018

GeneDx

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	-0.93
CADD	Benign	5.5
DANN	Benign	0.29
PhyloP100		-0.13
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs633762; hg19: chr6-70965125; COSMIC: COSV57878857; COSMIC: COSV57878857;