chr6-70254561-C-T

Position:

• chr6-70254561-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000357250.11(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 ENST00000357250.11 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0490

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL9A1	NM_001851.6	c.1666-32G>A		intron_variant		ENST00000357250.11	NP_001842.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL9A1	ENST00000357250.11	c.1666-32G>A		intron_variant		1	NM_001851.6	ENSP00000349790	P1

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

GnomAD3 exomes AF: 0.00877 AC: 2203 AN: 251212 Hom.: 18 AF XY: 0.00899 AC XY: 1220 AN XY: 135774

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 SAS exome AF: 0.00510

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

Gnomad4 AFR exome AF: 0.00159

Gnomad4 AMR exome AF: 0.00776

Gnomad4 ASJ exome AF: 0.0265

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00499

Gnomad4 FIN exome AF: 0.00558

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0117

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

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00621

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.0118 Hom.: 1

Bravo AF: 0.00745

Asia WGS AF: 0.00144 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.8
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs72923190; hg19: chr6-70964264;