6-33185723-G-A

Variant names:

• chr6-33185723-G-A
• rs747064765
• NM_080680.3:c.854C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_080680.3(COL11A2):​c.854C>T​(p.Thr285Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000264 in 1,361,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T285T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: COL11A2 NM_080680.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.49
• Publications: 2 publications found

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]

COL11A2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 13

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• nonsyndromic genetic hearing loss

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE Submitted by: ClinGen
• otospondylomegaepiphyseal dysplasia, autosomal dominant

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive nonsyndromic hearing loss 53

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• otospondylomegaepiphyseal dysplasia

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• otospondylomegaepiphyseal dysplasia, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fibrochondrogenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000305994 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.118229955).
• BP6: Variant 6-33185723-G-A is Benign according to our data. Variant chr6-33185723-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 228539.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080680.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A2	NM_080680.3	MANE Select	c.854C>T	p.Thr285Met	missense	Exon 6 of 66	NP_542411.2
	COL11A2	NM_001424108.1		c.854C>T	p.Thr285Met	missense	Exon 6 of 65	NP_001411037.1
	COL11A2	NM_001424109.1		c.8C>T	p.Thr3Met	missense	Exon 6 of 66	NP_001411038.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A2	ENST00000341947.7	TSL:5 MANE Select	c.854C>T	p.Thr285Met	missense	Exon 6 of 66	ENSP00000339915.2
	COL11A2	ENST00000930122.1		c.854C>T	p.Thr285Met	missense	Exon 6 of 65	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.799-669C>T		intron	N/A	ENSP00000363840.4

Frequencies

GnomAD3 genomes AF: 0.0000398 AC: 6 AN: 150940 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000365 AC: 9 AN: 246508 AF XY: 0.0000372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000361

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000248 AC: 30 AN: 1210650 Hom.: 0 Cov.: 29 AF XY: 0.0000233 AC XY: 14 AN XY: 600276

African (AFR) AF: 0.0000381 AC: 1 AN: 26214

American (AMR) AF: 0.000161 AC: 6 AN: 37278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16854

East Asian (EAS) AF: 0.00 AC: 0 AN: 16806

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4410

European-Non Finnish (NFE) AF: 0.0000210 AC: 20 AN: 950574

Other (OTH) AF: 0.0000456 AC: 2 AN: 43904

GnomAD4 genome AF: 0.0000398 AC: 6 AN: 150940 Hom.: 0 Cov.: 31 AF XY: 0.0000543 AC XY: 4 AN XY: 73604

African (AFR) AF: 0.00 AC: 0 AN: 40974

American (AMR) AF: 0.00 AC: 0 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67794

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000329 Hom.: 0

ExAC AF: 0.0000425 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.50	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.37	T
PhyloP100		2.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.25
Sift	Benign	0.20	T
Sift4G	Benign	0.095	T
Vest4		0.19
MVP		0.74
ClinPred		0.052	T
GERP RS		3.8
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs747064765; hg19: chr6-33153500; COSMIC: COSV59498730; COSMIC: COSV59498730;