rs12136577

chr1-103003211-A-T

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.1998+4T>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,612,950 control chromosomes in the GnomAD database, including 14,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1071 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13722 hom.)
• Consequence: COL11A1 NM_001854.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0003112
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.211

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=-0.56).
• BP6: Variant 1-103003211-A-T is Benign according to our data. Variant chr1-103003211-A-T is described in ClinVar as [Benign]. Clinvar id is 258440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-103003211-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A1	NM_001854.4	c.1998+4T>A		splice_donor_region_variant, intron_variant		ENST00000370096.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A1	ENST00000370096.9	c.1998+4T>A		splice_donor_region_variant, intron_variant		1	NM_001854.4	P1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16270 AN: 151944 Hom.: 1070 Cov.: 31

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0645

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.0919

GnomAD3 exomes AF: 0.123 AC: 30761 AN: 250108 Hom.: 2270 AF XY: 0.121 AC XY: 16360 AN XY: 135202

Gnomad AFR exome AF: 0.0477

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.00142

Gnomad SAS exome AF: 0.0711

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.132 AC: 192950 AN: 1460888 Hom.: 13722 Cov.: 34 AF XY: 0.131 AC XY: 95249 AN XY: 726696

Gnomad4 AFR exome AF: 0.0457

Gnomad4 AMR exome AF: 0.181

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.00244

Gnomad4 SAS exome AF: 0.0738

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.107 AC: 16276 AN: 152062 Hom.: 1071 Cov.: 31 AF XY: 0.107 AC XY: 7940 AN XY: 74350

Gnomad4 AFR AF: 0.0477

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.0645

Gnomad4 FIN AF: 0.161

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.0914

Alfa AF: 0.132 Hom.: 459

Bravo AF: 0.103

Asia WGS AF: 0.0400 AC: 137 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.137

ClinVar

Significance: Benign

Submissions summary: Benign:11

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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Fibrochondrogenesis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
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. -

Stickler syndrome type 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	11
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00031
dbscSNV1_RF	Benign	0.042
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: rs12136577; hg19: chr1-103468767;