chr1-102940336-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001854.4(COL11A1):c.3375C>G(p.Asp1125Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,612,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D1125D) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

COL11A1
NM_001854.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.833

Publications

18 publications found

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 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

COL11A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL11A1	NM_001854.4	MANE Select	c.3375C>G	p.Asp1125Glu	missense	Exon 43 of 67	NP_001845.3
COL11A1	NM_080629.3		c.3411C>G	p.Asp1137Glu	missense	Exon 43 of 67	NP_542196.2
COL11A1	NM_001190709.2		c.3258C>G	p.Asp1086Glu	missense	Exon 42 of 66	NP_001177638.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL11A1	ENST00000370096.9	TSL:1 MANE Select	c.3375C>G	p.Asp1125Glu	missense	Exon 43 of 67	ENSP00000359114.3
COL11A1	ENST00000512756.5	TSL:1	c.3027C>G	p.Asp1009Glu	missense	Exon 41 of 65	ENSP00000426533.1
COL11A1	ENST00000635193.1	TSL:1	n.*625C>G		non_coding_transcript_exon	Exon 40 of 64	ENSP00000489428.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

250784

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461046

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726868

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33464

American (AMR)

AF:

0.0000447

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111306

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151854

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74144

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41296

American (AMR)

AF:

0.0000656

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

2595

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1125 of the COL11A1 protein (p.Asp1125Glu). This variant is present in population databases (rs17127270, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with COL11A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1477869). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL11A1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Jan 03, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Intervertebral disc disorder;C0265235:Marshall syndrome;C1858084:Stickler syndrome type 2;C3278138:Fibrochondrogenesis 1;C4760307:Hearing loss, autosomal dominant 37

Uncertain:1

Dec 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.020

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Uncertain

0.62

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

1.2

PhyloP100

0.83

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.63

Sift

Benign

0.15

Sift4G

Benign

0.16

Polyphen

1.0

Vest4

0.57

MutPred

0.30

Gain of solvent accessibility (P = 0.0155)

MVP

0.89

MPC

0.11

ClinPred

0.49

GERP RS

-1.0

Varity_R

0.23

gMVP

0.078

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over