rs372250466

chr6-33164465-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_080680.3(COL11A2):c.4872C>T(p.Tyr1624=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,552,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: COL11A2 NM_080680.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.472

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 6-33164465-G-A is Benign according to our data. Variant chr6-33164465-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 356382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33164465-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.472 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000789 (12/152130) while in subpopulation EAS AF= 0.00116 (6/5178). AF 95% confidence interval is 0.000505. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A2	NM_080680.3	c.4872C>T	p.Tyr1624=	synonymous_variant	65/66	ENST00000341947.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A2	ENST00000341947.7	c.4872C>T	p.Tyr1624=	synonymous_variant	65/66	5	NM_080680.3	P4
COL11A2	ENST00000374708.8	c.4614C>T	p.Tyr1538=	synonymous_variant	63/64	5		A1
COL11A2	ENST00000477772.1	n.662C>T		non_coding_transcript_exon_variant	8/9	2
COL11A2	ENST00000683572.1	n.678C>T		non_coding_transcript_exon_variant	8/9

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000140 AC: 23 AN: 164608 Hom.: 0 AF XY: 0.000181 AC XY: 16 AN XY: 88538

Gnomad AFR exome AF: 0.000111

Gnomad AMR exome AF: 0.0000392

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00118

Gnomad SAS exome AF: 0.000129

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.0000336 AC: 47 AN: 1400004 Hom.: 0 Cov.: 32 AF XY: 0.0000420 AC XY: 29 AN XY: 689930

Gnomad4 AFR exome AF: 0.0000939

Gnomad4 AMR exome AF: 0.0000271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000435

Gnomad4 SAS exome AF: 0.0000749

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.000156

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74302

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000793

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Otospondylomegaepiphyseal dysplasia, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 09, 2016

p.Tyr1624Tyr in exon 65 of COL11A2: This variant is not expected to have clinica l significance because it does not alter an amino acid residue, and it is not lo cated within the splice consensus sequence. It has been identified in 0.4% (6/14 34) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs372250466). -

Nonsyndromic Hearing Loss, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Otospondylomegaepiphyseal dysplasia, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Fibrochondrogenesis 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Stickler Syndrome, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	3.0
Dann	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs372250466; hg19: chr6-33132242;