rs186245518

chr1-102913704-T-Achr1-102913704-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001854.4(COL11A1):c.3979-14A>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,611,876 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (62 hom.)
• Consequence: COL11A1 NM_001854.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -6.74

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=-0.93).
• BP6: Variant 1-102913704-T-A is Benign according to our data. Variant chr1-102913704-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 258463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-102913704-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00404 (615/152178) while in subpopulation SAS AF= 0.0127 (61/4818). AF 95% confidence interval is 0.0101. There are 3 homozygotes in gnomad4. There are 282 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL11A1	NM_001854.4	c.3979-14A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370096.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL11A1	ENST00000370096.9	c.3979-14A>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001854.4	P1

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 616 AN: 152058 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00653

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00521 AC: 1310 AN: 251270 Hom.: 14 AF XY: 0.00599 AC XY: 814 AN XY: 135796

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0149

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00617

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00640 AC: 9344 AN: 1459698 Hom.: 62 Cov.: 29 AF XY: 0.00662 AC XY: 4809 AN XY: 726338

Gnomad4 AFR exome AF: 0.000868

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.00305

Gnomad4 NFE exome AF: 0.00655

Gnomad4 OTH exome AF: 0.00733

GnomAD4 genome AF: 0.00404 AC: 615 AN: 152178 Hom.: 3 Cov.: 32 AF XY: 0.00379 AC XY: 282 AN XY: 74414

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0127

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00653

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00216 Hom.: 1

Bravo AF: 0.00354

Asia WGS AF: 0.00404 AC: 14 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	COL11A1: BS1, BS2 -

Fibrochondrogenesis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	0.0020
Dann	Benign	0.40

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

Other links and lift over

dbSNP: rs186245518; hg19: chr1-103379260;