6-70254561-C-T

Variant names:

• chr6-70254561-C-T
• rs72923190
• NM_001851.6:c.1666-32G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001851.6(COL9A1):​c.1666-32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,603,478 control chromosomes in the GnomAD database, including 109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (10 hom., cov: 32)
  • Exomes 𝑓: 0.011 (99 hom.)
• Consequence: COL9A1 NM_001851.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0490
• Publications: 3 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=-0.82).
• BP6: Variant 6-70254561-C-T is Benign according to our data. Variant chr6-70254561-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0074 (1127/152278) while in subpopulation NFE AF = 0.0114 (773/68012). AF 95% confidence interval is 0.0107. There are 10 homozygotes in GnomAd4. There are 547 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001851.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	NM_001851.6	MANE Select	c.1666-32G>A		intron	N/A	NP_001842.3
	COL9A1	NM_001377289.1		c.967-32G>A		intron	N/A	NP_001364218.1
	COL9A1	NM_078485.4		c.937-32G>A		intron	N/A	NP_511040.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL9A1	ENST00000357250.11	TSL:1 MANE Select	c.1666-32G>A		intron	N/A	ENSP00000349790.6
	COL9A1	ENST00000320755.12	TSL:1	c.937-32G>A		intron	N/A	ENSP00000315252.7
	COL9A1	ENST00000489861.2	TSL:3	n.51G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00741 AC: 1127 AN: 152160 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00621

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00877 AC: 2203 AN: 251212 AF XY: 0.00899

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00767

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00573

Gnomad NFE exome AF: 0.0112

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0105 AC: 15271 AN: 1451200 Hom.: 99 Cov.: 28 AF XY: 0.0103 AC XY: 7474 AN XY: 722850

African (AFR) AF: 0.00159 AC: 53 AN: 33294

American (AMR) AF: 0.00776 AC: 347 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 691 AN: 26068

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39610

South Asian (SAS) AF: 0.00499 AC: 429 AN: 86016

European-Finnish (FIN) AF: 0.00558 AC: 298 AN: 53402

Middle Eastern (MID) AF: 0.00886 AC: 51 AN: 5754

European-Non Finnish (NFE) AF: 0.0115 AC: 12700 AN: 1102306

Other (OTH) AF: 0.0117 AC: 701 AN: 60052

GnomAD4 genome AF: 0.00740 AC: 1127 AN: 152278 Hom.: 10 Cov.: 32 AF XY: 0.00735 AC XY: 547 AN XY: 74472

African (AFR) AF: 0.00173 AC: 72 AN: 41562

American (AMR) AF: 0.00432 AC: 66 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00621 AC: 30 AN: 4828

European-Finnish (FIN) AF: 0.00490 AC: 52 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 773 AN: 68012

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.0118 Hom.: 1

Bravo AF: 0.00745

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.8
DANN	Benign	0.76
PhyloP100		-0.049
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.080		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: rs72923190; hg19: chr6-70964264;