6-33185058-A-T

Position:

• chr6-33185058-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080680.3(COL11A2):​c.877-4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,548,026 control chromosomes in the GnomAD database, including 77,240 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7749 hom., cov: 31)
  • Exomes 𝑓: 0.31 (69491 hom.)
• Consequence: COL11A2 NM_080680.3 splice_region, intron
• Scores: Splicing: ADA: 0.00006490
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.525

Genes affected

COL11A2 (HGNC:2187): (collagen type XI alpha 2 chain) This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. It is located on chromosome 6 very close to but separate from the gene for retinoid X receptor beta. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Proteolytic processing of this type XI chain produces PARP, a proline/arginine-rich protein that is an amino terminal domain. Mutations in this gene are associated with type III Stickler syndrome, otospondylomegaepiphyseal dysplasia (OSMED syndrome), Weissenbacher-Zweymuller syndrome, autosomal dominant non-syndromic sensorineural type 13 deafness (DFNA13), and autosomal recessive non-syndromic sensorineural type 53 deafness (DFNB53). Alternative splicing results in multiple transcript variants. A related pseudogene is located nearby on chromosome 6. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 6-33185058-A-T is Benign according to our data. Variant chr6-33185058-A-T is described in ClinVar as [Benign]. Clinvar id is 46570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33185058-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A2	NM_080680.3	c.877-4T>A		splice_region_variant, intron_variant		ENST00000341947.7	NP_542411.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A2	ENST00000341947.7	c.877-4T>A		splice_region_variant, intron_variant		5	NM_080680.3	ENSP00000339915.2
COL11A2	ENST00000374708.8	c.799-4T>A		splice_region_variant, intron_variant		5		ENSP00000363840.4
COL11A2	ENST00000682718.1	n.694-4T>A		splice_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47886 AN: 151790 Hom.: 7746 Cov.: 31

Gnomad AFR AF: 0.361

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.313

Gnomad OTH AF: 0.323

GnomAD3 exomes AF: 0.298 AC: 46650 AN: 156324 Hom.: 7398 AF XY: 0.309 AC XY: 25455 AN XY: 82276

Gnomad AFR exome AF: 0.363

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.235

Gnomad SAS exome AF: 0.386

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.317

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.312 AC: 435227 AN: 1396118 Hom.: 69491 Cov.: 33 AF XY: 0.315 AC XY: 216676 AN XY: 688746

Gnomad4 AFR exome AF: 0.388

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.374

Gnomad4 EAS exome AF: 0.229

Gnomad4 SAS exome AF: 0.386

Gnomad4 FIN exome AF: 0.218

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.313

GnomAD4 genome AF: 0.315 AC: 47903 AN: 151908 Hom.: 7749 Cov.: 31 AF XY: 0.310 AC XY: 22997 AN XY: 74248

Gnomad4 AFR AF: 0.361

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.227

Gnomad4 SAS AF: 0.383

Gnomad4 FIN AF: 0.204

Gnomad4 NFE AF: 0.313

Gnomad4 OTH AF: 0.321

Alfa AF: 0.320 Hom.: 2507

Bravo AF: 0.318

Asia WGS AF: 0.329 AC: 1144 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	877-4T>A in Intron 06 of COL11A2: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 32.8% (1000/3050) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs1799907). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Otospondylomegaepiphyseal dysplasia, autosomal recessive Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -

Fibrochondrogenesis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Autosomal recessive nonsyndromic hearing loss 53 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Autosomal dominant nonsyndromic hearing loss 13 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Stickler Syndrome, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 30, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	10
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000065
dbscSNV1_RF	Benign	0.0020
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: rs1799907; hg19: chr6-33152835;