rs772567850

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_080680.3(COL11A2):​c.4559G>A​(p.Arg1520His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000385 in 1,611,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

COL11A2
NM_080680.3 missense

Scores

2
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.25
Variant links:
Genes affected
COL11A2 (HGNC:2187): (collagen type XI alpha 2 chain) This gene encodes one of the two alpha chains of type XI collagen, a minor fibrillar collagen. It is located on chromosome 6 very close to but separate from the gene for retinoid X receptor beta. Type XI collagen is a heterotrimer but the third alpha chain is a post-translationally modified alpha 1 type II chain. Proteolytic processing of this type XI chain produces PARP, a proline/arginine-rich protein that is an amino terminal domain. Mutations in this gene are associated with type III Stickler syndrome, otospondylomegaepiphyseal dysplasia (OSMED syndrome), Weissenbacher-Zweymuller syndrome, autosomal dominant non-syndromic sensorineural type 13 deafness (DFNA13), and autosomal recessive non-syndromic sensorineural type 53 deafness (DFNB53). Alternative splicing results in multiple transcript variants. A related pseudogene is located nearby on chromosome 6. [provided by RefSeq, Jul 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.21223846).
BP6
Variant 6-33165740-C-T is Benign according to our data. Variant chr6-33165740-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228536.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL11A2NM_080680.3 linkc.4559G>A p.Arg1520His missense_variant Exon 63 of 66 ENST00000341947.7 NP_542411.2 P13942A0A0C4DFS1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL11A2ENST00000341947.7 linkc.4559G>A p.Arg1520His missense_variant Exon 63 of 66 5 NM_080680.3 ENSP00000339915.2 A0A0C4DFS1
COL11A2ENST00000374708.8 linkc.4301G>A p.Arg1434His missense_variant Exon 61 of 64 5 ENSP00000363840.4 Q4VXY6
COL11A2ENST00000477772.1 linkn.349G>A non_coding_transcript_exon_variant Exon 6 of 9 2
COL11A2ENST00000683572.1 linkn.365G>A non_coding_transcript_exon_variant Exon 6 of 9

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152102
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000387
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000377
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000442
AC:
11
AN:
248738
Hom.:
0
AF XY:
0.0000446
AC XY:
6
AN XY:
134578
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000358
Gnomad NFE exome
AF:
0.0000353
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000356
AC:
52
AN:
1459462
Hom.:
0
Cov.:
34
AF XY:
0.0000386
AC XY:
28
AN XY:
726072
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000196
Gnomad4 NFE exome
AF:
0.0000333
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000657
AC:
10
AN:
152220
Hom.:
0
Cov.:
31
AF XY:
0.0000403
AC XY:
3
AN XY:
74406
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000377
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000865
Hom.:
0
Bravo
AF:
0.0000302
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 17, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Arg1520His variant in COL11A2 has not been previously reported in individu als with hearing loss, but has been identified in 2/65948 of European chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Al though this variant has been seen in the general population, its frequency is no t high enough to rule out a pathogenic role. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg1520His variant i s uncertain. -

Conductive hearing impairment;C0424731:Single transverse palmar crease;C0426501:Short lingual frenulum;C1849937:Disproportionate short-limb short stature;C1865014:Long philtrum;C2243051:Macrocephaly;C2674432:Reduced bone mineral density;C3697248:Short chin;C4011556:Abnormal eyebrow morphology Uncertain:1
Aug 18, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:1
Nov 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.067
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.020
T;T;.
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.069
FATHMM_MKL
Benign
0.43
N
M_CAP
Uncertain
0.095
D
MetaRNN
Benign
0.21
T;T;T
MetaSVM
Benign
-0.66
T
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.0
N;N;N
REVEL
Benign
0.24
Sift
Benign
0.059
T;T;T
Sift4G
Benign
0.10
T;T;T
Vest4
0.42
MVP
0.42
MPC
0.42
ClinPred
0.33
T
GERP RS
1.3
gMVP
0.31

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.

Other links and lift over

dbSNP: rs772567850; hg19: chr6-33133517; COSMIC: COSV100554476; API