rs17127270

Positions:

• chr1-102940336-G-A
• chr1-102940336-G-C
• chr1-102940336-G-T

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.3375C>T​(p.Asp1125=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,611,018 control chromosomes in the GnomAD database, including 22,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2161 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20428 hom.)
• Consequence: COL11A1 NM_001854.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.833

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=-0.53).
• BP6: Variant 1-102940336-G-A is Benign according to our data. Variant chr1-102940336-G-A is described in ClinVar as [Benign]. Clinvar id is 258458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-102940336-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.833 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A1	NM_001854.4	c.3375C>T	p.Asp1125=	synonymous_variant	43/67	ENST00000370096.9	NP_001845.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A1	ENST00000370096.9	c.3375C>T	p.Asp1125=	synonymous_variant	43/67	1	NM_001854.4	ENSP00000359114	P1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24768 AN: 151802 Hom.: 2159 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.0944

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0156

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.142

GnomAD3 exomes AF: 0.141 AC: 35409 AN: 250784 Hom.: 3009 AF XY: 0.143 AC XY: 19393 AN XY: 135590

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.0602

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.0120

Gnomad SAS exome AF: 0.135

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.142

GnomAD4 exome AF: 0.162 AC: 235924 AN: 1459098 Hom.: 20428 Cov.: 31 AF XY: 0.161 AC XY: 117049 AN XY: 725980

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.0642

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.0104

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.163 AC: 24795 AN: 151920 Hom.: 2161 Cov.: 32 AF XY: 0.161 AC XY: 11982 AN XY: 74246

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.0942

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.0157

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.142

Alfa AF: 0.155 Hom.: 2191

Bravo AF: 0.157

Asia WGS AF: 0.0870 AC: 303 AN: 3478

EpiCase AF: 0.156

EpiControl AF: 0.157

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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 07, 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	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	-0.53
CADD	Benign	0.68
DANN	Benign	0.28

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: rs17127270; hg19: chr1-103405892; COSMIC: COSV62189732;