1-102886895-A-G

Position:

• chr1-102886895-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001854.4(COL11A1):​c.4770T>C​(p.Ile1590=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 1,613,456 control chromosomes in the GnomAD database, including 289,481 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (21765 hom., cov: 31)
  • Exomes 𝑓: 0.60 (267716 hom.)
• Consequence: COL11A1 NM_001854.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.790

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 1-102886895-A-G is Benign according to our data. Variant chr1-102886895-A-G is described in ClinVar as [Benign]. Clinvar id is 258470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-102886895-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.646 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A1	NM_001854.4	c.4770T>C	p.Ile1590=	synonymous_variant	63/67	ENST00000370096.9	NP_001845.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A1	ENST00000370096.9	c.4770T>C	p.Ile1590=	synonymous_variant	63/67	1	NM_001854.4	ENSP00000359114	P1

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74268 AN: 151790 Hom.: 21753 Cov.: 31

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.564

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.639

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.617

Gnomad OTH AF: 0.521

GnomAD3 exomes AF: 0.593 AC: 149024 AN: 251204 Hom.: 46721 AF XY: 0.596 AC XY: 80956 AN XY: 135750

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.734

Gnomad ASJ exome AF: 0.556

Gnomad EAS exome AF: 0.638

Gnomad SAS exome AF: 0.571

Gnomad FIN exome AF: 0.648

Gnomad NFE exome AF: 0.609

Gnomad OTH exome AF: 0.611

GnomAD4 exome AF: 0.600 AC: 876350 AN: 1461548 Hom.: 267716 Cov.: 52 AF XY: 0.600 AC XY: 436366 AN XY: 727072

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.724

Gnomad4 ASJ exome AF: 0.556

Gnomad4 EAS exome AF: 0.630

Gnomad4 SAS exome AF: 0.573

Gnomad4 FIN exome AF: 0.649

Gnomad4 NFE exome AF: 0.610

Gnomad4 OTH exome AF: 0.584

GnomAD4 genome AF: 0.489 AC: 74287 AN: 151908 Hom.: 21765 Cov.: 31 AF XY: 0.496 AC XY: 36817 AN XY: 74228

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.657

Gnomad4 ASJ AF: 0.564

Gnomad4 EAS AF: 0.665

Gnomad4 SAS AF: 0.569

Gnomad4 FIN AF: 0.639

Gnomad4 NFE AF: 0.617

Gnomad4 OTH AF: 0.525

Alfa AF: 0.584 Hom.: 43409

Bravo AF: 0.477

Asia WGS AF: 0.591 AC: 2050 AN: 3476

EpiCase AF: 0.605

EpiControl AF: 0.604

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 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, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Benign:2

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

Stickler syndrome type 2 Benign:2

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. -
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	-0.68
CADD	Benign	0.24
DANN	Benign	0.68

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: rs2229783; hg19: chr1-103352451; COSMIC: COSV62176448; COSMIC: COSV62176448;