1-40300870-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001852.4(COL9A2):c.*312T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.047 in 320,982 control chromosomes in the GnomAD database, including 799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.065 (615 hom., cov: 32)
  • Exomes 𝑓: 0.031 (184 hom.)
• Consequence: COL9A2 NM_001852.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.29

Genes affected

COL9A2 (HGNC:2218): (collagen type IX alpha 2 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. This chain is unusual in that, unlike the other two type IX alpha chains, it contains a covalently attached glycosaminoglycan side chain. Mutations in this gene are associated with multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-40300870-A-T is Benign according to our data. Variant chr1-40300870-A-T is described in ClinVar as [Benign]. Clinvar id is 297285.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL9A2	NM_001852.4	c.*312T>A		3_prime_UTR_variant	32/32	ENST00000372748.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL9A2	ENST00000372748.8	c.*312T>A		3_prime_UTR_variant	32/32	1	NM_001852.4	P1
COL9A2	ENST00000482722.5	n.2685T>A		non_coding_transcript_exon_variant	31/31	1

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9864 AN: 152054 Hom.: 608 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0424

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.0258

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.0229

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0430

GnomAD4 exome AF: 0.0308 AC: 5194 AN: 168810 Hom.: 184 Cov.: 0 AF XY: 0.0305 AC XY: 2697 AN XY: 88356

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.0508

Gnomad4 ASJ exome AF: 0.0359

Gnomad4 EAS exome AF: 0.0328

Gnomad4 SAS exome AF: 0.0324

Gnomad4 FIN exome AF: 0.0254

Gnomad4 NFE exome AF: 0.0213

Gnomad4 OTH exome AF: 0.0345

GnomAD4 genome AF: 0.0651 AC: 9903 AN: 152172 Hom.: 615 Cov.: 32 AF XY: 0.0653 AC XY: 4859 AN XY: 74390

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.0423

Gnomad4 ASJ AF: 0.0409

Gnomad4 EAS AF: 0.0259

Gnomad4 SAS AF: 0.0344

Gnomad4 FIN AF: 0.0229

Gnomad4 NFE AF: 0.0214

Gnomad4 OTH AF: 0.0458

Alfa AF: 0.0541 Hom.: 49

Bravo AF: 0.0706

Asia WGS AF: 0.0670 AC: 231 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epiphyseal dysplasia, multiple, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.28
Dann	Benign	0.46

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

LitVar

Other links and lift over

dbSNP: rs41466547; hg19: chr1-40766542;