rs387906611

Variant names:

• chr1-102989562-C-G
• rs387906611
• NM_001854.4:c.2350G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000370096.9(COL11A1):​c.2350G>C​(p.Gly784Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: COL11A1 ENST00000370096.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.27
• Publications: 6 publications found

Genes affected

COL11A1 (HGNC:2186): (collagen type XI alpha 1 chain) This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Mutations in this gene are associated with type II Stickler syndrome and with Marshall syndrome. A single-nucleotide polymorphism in this gene is also associated with susceptibility to lumbar disc herniation. Multiple transcript variants have been identified for this gene. [provided by RefSeq, Nov 2009]

COL11A1 Gene-Disease associations (from GenCC):

• Marshall syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Stickler syndrome type 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet, Genomics England PanelApp
• fibrochondrogenesis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal dominant 37

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 1-102989562-C-G is Pathogenic according to our data. Variant chr1-102989562-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 29648.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000370096.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A1	NM_001854.4	MANE Select	c.2350G>C	p.Gly784Arg	missense	Exon 29 of 67	NP_001845.3
	COL11A1	NM_080629.3		c.2386G>C	p.Gly796Arg	missense	Exon 29 of 67	NP_542196.2
	COL11A1	NM_001190709.2		c.2233G>C	p.Gly745Arg	missense	Exon 28 of 66	NP_001177638.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A1	ENST00000370096.9	TSL:1 MANE Select	c.2350G>C	p.Gly784Arg	missense	Exon 29 of 67	ENSP00000359114.3
	COL11A1	ENST00000512756.5	TSL:1	c.2002G>C	p.Gly668Arg	missense	Exon 27 of 65	ENSP00000426533.1
	COL11A1	ENST00000635193.1	TSL:1	n.1666G>C		non_coding_transcript_exon	Exon 25 of 64	ENSP00000489428.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Fibrochondrogenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.98		Gain of MoRF binding (P = 0.0191)
MVP		0.98
MPC		0.14
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs387906611; hg19: chr1-103455118;