rs1676486

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001854.4(COL11A1):c.4603T>C(p.Ser1535Pro) variant causes a missense change. The variant allele was found at a frequency of 0.802 in 1,612,246 control chromosomes in the GnomAD database, including 519,995 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1535L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.81 ( 50267 hom., cov: 32)

Exomes 𝑓: 0.80 ( 469728 hom. )

Consequence

COL11A1
NM_001854.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14O:1

Conservation

PhyloP100: 5.47

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2520567E-6).

BP6

Variant 1-102888582-A-G is Benign according to our data. Variant chr1-102888582-A-G is described in ClinVar as [Benign]. Clinvar id is 17137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-102888582-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A1	NM_001854.4 linkuse as main transcript	c.4603T>C	p.Ser1535Pro	missense_variant	62/67	ENST00000370096.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A1	ENST00000370096.9 linkuse as main transcript	c.4603T>C	p.Ser1535Pro	missense_variant	62/67	1	NM_001854.4	P1	P12107-1

Frequencies

GnomAD3 genomes

AF:

0.812

AC:

123471

AN:

152046

Hom.:

50220

Cov.:

show subpopulations

Gnomad AFR

AF:

0.805

Gnomad AMI

AF:

0.803

Gnomad AMR

AF:

0.868

Gnomad ASJ

AF:

0.825

Gnomad EAS

AF:

0.749

Gnomad SAS

AF:

0.666

Gnomad FIN

AF:

0.865

Gnomad MID

AF:

0.851

Gnomad NFE

AF:

0.810

Gnomad OTH

AF:

0.830

GnomAD3 exomes

AF:

0.799

AC:

200324

AN:

250612

Hom.:

80666

AF XY:

0.792

AC XY:

107339

AN XY:

135502

show subpopulations

Gnomad AFR exome

AF:

0.807

Gnomad AMR exome

AF:

0.873

Gnomad ASJ exome

AF:

0.820

Gnomad EAS exome

AF:

0.726

Gnomad SAS exome

AF:

0.669

Gnomad FIN exome

AF:

0.861

Gnomad NFE exome

AF:

0.808

Gnomad OTH exome

AF:

0.817

GnomAD4 exome

AF:

0.801

AC:

1169051

AN:

1460082

Hom.:

469728

Cov.:

AF XY:

0.797

AC XY:

578837

AN XY:

726364

show subpopulations

Gnomad4 AFR exome

AF:

0.802

Gnomad4 AMR exome

AF:

0.874

Gnomad4 ASJ exome

AF:

0.820

Gnomad4 EAS exome

AF:

0.704

Gnomad4 SAS exome

AF:

0.674

Gnomad4 FIN exome

AF:

0.856

Gnomad4 NFE exome

AF:

0.808

Gnomad4 OTH exome

AF:

0.804

GnomAD4 genome

AF:

0.812

AC:

123577

AN:

152164

Hom.:

50267

Cov.:

AF XY:

0.813

AC XY:

60462

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.805

Gnomad4 AMR

AF:

0.868

Gnomad4 ASJ

AF:

0.825

Gnomad4 EAS

AF:

0.749

Gnomad4 SAS

AF:

0.665

Gnomad4 FIN

AF:

0.865

Gnomad4 NFE

AF:

0.810

Gnomad4 OTH

AF:

0.832

Alfa

AF:

0.812

Hom.:

79548

Bravo

AF:

0.818

TwinsUK

AF:

0.794

AC:

2946

ALSPAC

AF:

0.809

AC:

3116

ESP6500AA

AF:

0.799

AC:

3519

ESP6500EA

AF:

0.811

AC:

6977

ExAC

AF:

0.794

AC:

96377

Asia WGS

AF:

0.737

AC:

2563

AN:

3478

EpiCase

AF:

0.810

EpiControl

AF:

0.814

ClinVar

Significance: Benign

Submissions summary: Benign:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	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. -

Fibrochondrogenesis 1

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Stickler syndrome type 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Hearing loss, autosomal dominant 37

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Marshall syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Connective tissue disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 18, 2022

- -

Lumbar disk herniation, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Benign

0.67

DEOGEN2

Benign

0.27

T;.;.;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.053

T;T;T;T

MetaRNN

Benign

0.0000013

T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-1.4

N;.;.;.

MutationTaster

Benign

0.60

P;P;P;P

PrimateAI

Uncertain

0.64

PROVEAN

Benign

5.0

N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

1.0

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;B;B;.

Vest4

0.11

MPC

0.15

ClinPred

0.014

GERP RS

5.7

Varity_R

0.11

gMVP

0.28

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over