NM_080680.3:c.4521G>A

Variant names:

• chr6-33165778-C-T
• rs114580597
• NM_080680.3:c.4521G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_080680.3(COL11A2):​c.4521G>A​(p.Gln1507Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00307 in 1,613,348 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (9 hom.)
• Consequence: COL11A2 NM_080680.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.82
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 6-33165778-C-T is Benign according to our data. Variant chr6-33165778-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 162977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00177 (269/152254) while in subpopulation NFE AF = 0.00318 (216/68016). AF 95% confidence interval is 0.00283. There are 0 homozygotes in GnomAd4. There are 105 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

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.4521G>A	p.Gln1507Gln	synonymous	Exon 63 of 66	NP_542411.2
	COL11A2	NM_001424108.1		c.4341G>A	p.Gln1447Gln	synonymous	Exon 62 of 65	NP_001411037.1
	COL11A2	NM_080681.3		c.4263G>A	p.Gln1421Gln	synonymous	Exon 61 of 64	NP_542412.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A2	ENST00000341947.7	TSL:5 MANE Select	c.4521G>A	p.Gln1507Gln	synonymous	Exon 63 of 66	ENSP00000339915.2
	COL11A2	ENST00000930122.1		c.4341G>A	p.Gln1447Gln	synonymous	Exon 62 of 65	ENSP00000600181.1
	COL11A2	ENST00000374708.8	TSL:5	c.4263G>A	p.Gln1421Gln	synonymous	Exon 61 of 64	ENSP00000363840.4

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00318

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00162 AC: 404 AN: 250102 AF XY: 0.00177

Gnomad AFR exome AF: 0.000741

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00110

Gnomad NFE exome AF: 0.00297

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00320 AC: 4678 AN: 1461094 Hom.: 9 Cov.: 34 AF XY: 0.00310 AC XY: 2254 AN XY: 726772

African (AFR) AF: 0.000597 AC: 20 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86258

European-Finnish (FIN) AF: 0.000969 AC: 51 AN: 52636

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00400 AC: 4449 AN: 1112002

Other (OTH) AF: 0.00190 AC: 115 AN: 60390

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152254 Hom.: 0 Cov.: 31 AF XY: 0.00141 AC XY: 105 AN XY: 74442

African (AFR) AF: 0.000890 AC: 37 AN: 41556

American (AMR) AF: 0.000327 AC: 5 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00318 AC: 216 AN: 68016

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00212 Hom.: 0

Bravo AF: 0.00178

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00261

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	2	Connective tissue disorder (2)
-	-	1	Fibrochondrogenesis 2 (1)
-	-	1	Otospondylomegaepiphyseal dysplasia, autosomal dominant (1)
-	-	1	Otospondylomegaepiphyseal dysplasia, autosomal recessive (1)
-	-	1	Stickler Syndrome, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.9
DANN	Benign	0.78
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114580597; hg19: chr6-33133555;