NM_001854.4:c.4770T>C

Variant names:

• chr1-102886895-A-G
• rs2229783
• NM_001854.4:c.4770T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001854.4(COL11A1):​c.4770T>C​(p.Ile1590Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,613,456 control chromosomes in the GnomAD database, including 289,481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (21765 hom., cov: 31)
  • Exomes 𝑓: 0.60 (267716 hom.)
• Consequence: COL11A1 NM_001854.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.790
• Publications: 40 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-102886895-A-G is Benign according to our data. Variant chr1-102886895-A-G is described in ClinVar as Benign. ClinVar VariationId is 258470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001854.4. 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.4770T>C	p.Ile1590Ile	synonymous	Exon 63 of 67	NP_001845.3
	COL11A1	NM_080629.3		c.4806T>C	p.Ile1602Ile	synonymous	Exon 63 of 67	NP_542196.2
	COL11A1	NM_001190709.2		c.4653T>C	p.Ile1551Ile	synonymous	Exon 62 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.4770T>C	p.Ile1590Ile	synonymous	Exon 63 of 67	ENSP00000359114.3
	COL11A1	ENST00000512756.5	TSL:1	c.4422T>C	p.Ile1474Ile	synonymous	Exon 61 of 65	ENSP00000426533.1
	COL11A1	ENST00000635193.1	TSL:1	n.*2020T>C		non_coding_transcript_exon	Exon 60 of 64	ENSP00000489428.1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74268 AN: 151790 Hom.: 21753 Cov.: 31

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.564

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.521

GnomAD2 exomes AF: 0.593 AC: 149024 AN: 251204 AF XY: 0.596

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.734

Gnomad ASJ exome AF: 0.556

Gnomad EAS exome AF: 0.638

Gnomad FIN exome AF: 0.648

Gnomad NFE exome AF: 0.609

Gnomad OTH exome AF: 0.611

GnomAD4 exome AF: 0.600 AC: 876350 AN: 1461548 Hom.: 267716 Cov.: 52 AF XY: 0.600 AC XY: 436366 AN XY: 727072

African (AFR) AF: 0.117 AC: 3912 AN: 33464

American (AMR) AF: 0.724 AC: 32351 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 14527 AN: 26126

East Asian (EAS) AF: 0.630 AC: 25017 AN: 39682

South Asian (SAS) AF: 0.573 AC: 49459 AN: 86256

European-Finnish (FIN) AF: 0.649 AC: 34643 AN: 53414

Middle Eastern (MID) AF: 0.562 AC: 3237 AN: 5764

European-Non Finnish (NFE) AF: 0.610 AC: 677943 AN: 1111760

Other (OTH) AF: 0.584 AC: 35261 AN: 60376

GnomAD4 genome AF: 0.489 AC: 74287 AN: 151908 Hom.: 21765 Cov.: 31 AF XY: 0.496 AC XY: 36817 AN XY: 74228

African (AFR) AF: 0.137 AC: 5694 AN: 41470

American (AMR) AF: 0.657 AC: 10010 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 1957 AN: 3468

East Asian (EAS) AF: 0.665 AC: 3408 AN: 5128

South Asian (SAS) AF: 0.569 AC: 2741 AN: 4816

European-Finnish (FIN) AF: 0.639 AC: 6726 AN: 10526

Middle Eastern (MID) AF: 0.565 AC: 166 AN: 294

European-Non Finnish (NFE) AF: 0.617 AC: 41900 AN: 67958

Other (OTH) AF: 0.525 AC: 1107 AN: 2108

Alfa AF: 0.574 Hom.: 51869

Bravo AF: 0.477

Asia WGS AF: 0.591 AC: 2050 AN: 3476

EpiCase AF: 0.605

EpiControl AF: 0.604

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Sep 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Fibrochondrogenesis 1 Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Stickler syndrome type 2 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hearing loss, autosomal dominant 37 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Marshall syndrome Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.24
DANN	Benign	0.68
PhyloP100		-0.79
Mutation Taster		=93/7	polymorphism (auto)

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: rs2229783; hg19: chr1-103352451; COSMIC: COSV62176448; COSMIC: COSV62176448;