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rs147637674

chr1-102913637-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_001854.4(COL11A1):c.4032G>A(p.Pro1344=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,020 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

COL11A1
NM_001854.4 splice_region, synonymous

Scores

2
Splicing: ADA: 0.2116
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 0.0170
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.52).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-102913637-C-T is Benign according to our data. Variant chr1-102913637-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166922.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=3}. Variant chr1-102913637-C-T is described in Lovd as [Likely_benign].
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.017 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000611 (93/152186) while in subpopulation NFE AF= 0.00112 (76/67994). AF 95% confidence interval is 0.000915. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL11A1NM_001854.4 linkuse as main transcriptc.4032G>A p.Pro1344= splice_region_variant, synonymous_variant 53/67 ENST00000370096.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL11A1ENST00000370096.9 linkuse as main transcriptc.4032G>A p.Pro1344= splice_region_variant, synonymous_variant 53/671 NM_001854.4 P1P12107-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000618
AC:
94
AN:
152068
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.0000945
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00112
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000764
AC:
192
AN:
251342
Hom.:
1
AF XY:
0.000854
AC XY:
116
AN XY:
135842
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000637
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS exome
AF:
0.00134
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.00105
Gnomad OTH exome
AF:
0.000652
GnomAD4 exome
AF:
0.00117
AC:
1706
AN:
1460834
Hom.:
2
Cov.:
30
AF XY:
0.00121
AC XY:
878
AN XY:
726802
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
Gnomad4 AMR exome
AF:
0.000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000152
Gnomad4 SAS exome
AF:
0.00103
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.00135
Gnomad4 OTH exome
AF:
0.00114
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000611
AC:
93
AN:
152186
Hom.:
0
Cov.:
32
AF XY:
0.000470
AC XY:
35
AN XY:
74398
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.000327
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.0000945
Gnomad4 NFE
AF:
0.00112
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000911
Hom.:
1
Bravo
AF:
0.000472
EpiCase
AF:
0.00120
EpiControl
AF:
0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:2
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2022COL11A1: BP4, BP7 -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 26, 2024This sequence change affects codon 1344 of the COL11A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL11A1 protein. This variant also falls at the last nucleotide of exon 53, which is part of the consensus splice site for this exon. This variant is present in population databases (rs147637674, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 166922). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 02, 2014- -
Likely benign, criteria provided, single submitterclinical testingGeneDxJan 29, 2021- -
Fibrochondrogenesis 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Stickler syndrome type 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Connective tissue disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingCenter for Human Genetics, Inc, Center for Human Genetics, IncJun 01, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.52
Cadd
Benign
15
Dann
Benign
0.40

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.21
dbscSNV1_RF
Benign
0.54
SpliceAI score (max)
0.050
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: rs147637674; hg19: chr1-103379193; API