rs11164663

Variant names:

• chr1-103082941-A-C
• rs11164663
• NM_001854.4:c.138T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001854.4(COL11A1):​c.138T>G​(p.Asp46Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0758 in 1,612,862 control chromosomes in the GnomAD database, including 5,153 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (599 hom., cov: 31)
  • Exomes 𝑓: 0.075 (4554 hom.)
• Consequence: COL11A1 NM_001854.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.13
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025791824).
• BP6: Variant 1-103082941-A-C is Benign according to our data. Variant chr1-103082941-A-C is described in ClinVar as [Benign]. Clinvar id is 258438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A1	NM_001854.4	c.138T>G	p.Asp46Glu	missense_variant	Exon 2 of 67	ENST00000370096.9	NP_001845.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A1	ENST00000370096.9	c.138T>G	p.Asp46Glu	missense_variant	Exon 2 of 67	1	NM_001854.4	ENSP00000359114.3

Frequencies

GnomAD3 genomes AF: 0.0833 AC: 12658 AN: 151946 Hom.: 598 Cov.: 31

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0552

Gnomad ASJ AF: 0.0528

Gnomad EAS AF: 0.0120

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0616

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0781

Gnomad OTH AF: 0.0783

GnomAD2 exomes AF: 0.0612 AC: 15343 AN: 250700 AF XY: 0.0589

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0539

Gnomad EAS exome AF: 0.00865

Gnomad FIN exome AF: 0.0609

Gnomad NFE exome AF: 0.0787

Gnomad OTH exome AF: 0.0614

GnomAD4 exome AF: 0.0750 AC: 109519 AN: 1460798 Hom.: 4554 Cov.: 32 AF XY: 0.0730 AC XY: 53054 AN XY: 726686

African (AFR) AF: 0.133 AC: 4460 AN: 33426

American (AMR) AF: 0.0354 AC: 1582 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 1459 AN: 26086

East Asian (EAS) AF: 0.00885 AC: 351 AN: 39650

South Asian (SAS) AF: 0.0250 AC: 2155 AN: 86102

European-Finnish (FIN) AF: 0.0610 AC: 3254 AN: 53376

Middle Eastern (MID) AF: 0.0533 AC: 307 AN: 5762

European-Non Finnish (NFE) AF: 0.0825 AC: 91706 AN: 1111394

Other (OTH) AF: 0.0704 AC: 4245 AN: 60338

GnomAD4 genome AF: 0.0833 AC: 12672 AN: 152064 Hom.: 599 Cov.: 31 AF XY: 0.0818 AC XY: 6083 AN XY: 74360

African (AFR) AF: 0.128 AC: 5311 AN: 41472

American (AMR) AF: 0.0551 AC: 841 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 183 AN: 3468

East Asian (EAS) AF: 0.0118 AC: 61 AN: 5172

South Asian (SAS) AF: 0.0218 AC: 105 AN: 4822

European-Finnish (FIN) AF: 0.0616 AC: 653 AN: 10604

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0781 AC: 5310 AN: 67952

Other (OTH) AF: 0.0789 AC: 166 AN: 2104

Alfa AF: 0.0790 Hom.: 2240

Bravo AF: 0.0856

TwinsUK AF: 0.0863 AC: 320

ALSPAC AF: 0.0851 AC: 328

ESP6500AA AF: 0.132 AC: 580

ESP6500EA AF: 0.0820 AC: 705

ExAC AF: 0.0635 AC: 7703

Asia WGS AF: 0.0460 AC: 160 AN: 3476

EpiCase AF: 0.0731

EpiControl AF: 0.0718

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Oct 06, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

Fibrochondrogenesis 1 Benign:1

Jan 13, 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. -

Stickler syndrome type 2 Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	20
DANN	Benign	0.71
DEOGEN2	Benign	0.24	T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T;T;D;T;T;T;T;T;T
MetaRNN	Benign	0.0026	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.41	N;N;N;N;.;.;.;.;.
PhyloP100		1.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.44	N;N;N;N;.;.;.;.;N
REVEL	Benign	0.13
Sift	Benign	0.74	T;T;T;T;.;.;.;.;T
Sift4G	Benign	1.0	T;T;T;T;.;.;.;.;.
Polyphen		0.0	B;B;B;.;.;.;.;.;.
Vest4		0.083
MutPred		0.28		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MPC		0.31
ClinPred		0.019	T
GERP RS		3.0
PromoterAI		0.073	Neutral
Varity_R		0.038
gMVP		0.18
Mutation Taster		=100/0	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: rs11164663; hg19: chr1-103548497;