rs12136865

Positions:

• chr1-103078878-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001854.4(COL11A1):​c.275-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,584,692 control chromosomes in the GnomAD database, including 19,380 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1593 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17787 hom.)
• Consequence: COL11A1 NM_001854.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003413
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.36

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-103078878-A-G is Benign according to our data. Variant chr1-103078878-A-G is described in ClinVar as [Benign]. Clinvar id is 258452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-103078878-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A1	NM_001854.4	c.275-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000370096.9	NP_001845.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A1	ENST00000370096.9	c.275-7T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001854.4	ENSP00000359114	P1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20903 AN: 151990 Hom.: 1591 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.00887

Gnomad SAS AF: 0.0907

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.149 AC: 34605 AN: 232020 Hom.: 2851 AF XY: 0.147 AC XY: 18462 AN XY: 125960

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.00654

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.154 AC: 220279 AN: 1432584 Hom.: 17787 Cov.: 27 AF XY: 0.153 AC XY: 108832 AN XY: 713402

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.142

Gnomad4 EAS exome AF: 0.00689

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.207

Gnomad4 NFE exome AF: 0.160

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.138 AC: 20926 AN: 152108 Hom.: 1593 Cov.: 32 AF XY: 0.138 AC XY: 10274 AN XY: 74352

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.00889

Gnomad4 SAS AF: 0.0908

Gnomad4 FIN AF: 0.206

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.127

Alfa AF: 0.149 Hom.: 780

Bravo AF: 0.134

Asia WGS AF: 0.0590 AC: 204 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 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:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Stickler syndrome type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.8
DANN	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.030
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

Other links and lift over

dbSNP: rs12136865; hg19: chr1-103544434;