rs71664966

Variant names:

• chr1-103031236-A-G
• rs71664966
• NM_001854.4:c.660T>C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001854.4(COL11A1):​c.660T>C​(p.Ile220Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0668 in 1,560,958 control chromosomes in the GnomAD database, including 3,699 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (534 hom., cov: 30)
  • Exomes 𝑓: 0.064 (3165 hom.)
• Consequence: COL11A1 NM_001854.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.05

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 1-103031236-A-G is Benign according to our data. Variant chr1-103031236-A-G is described in ClinVar as [Benign]. Clinvar id is 93969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-103031236-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.05 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A1	NM_001854.4	c.660T>C	p.Ile220Ile	synonymous_variant	Exon 5 of 67	ENST00000370096.9	NP_001845.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A1	ENST00000370096.9	c.660T>C	p.Ile220Ile	synonymous_variant	Exon 5 of 67	1	NM_001854.4	ENSP00000359114.3

Frequencies

GnomAD3 genomes AF: 0.111 AC: 11906 AN: 107652 Hom.: 531 Cov.: 30

Gnomad AFR AF: 0.144

Gnomad AMI AF: 0.00629

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0949

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.0812

Gnomad OTH AF: 0.124

GnomAD3 exomes AF: 0.0706 AC: 16976 AN: 240598 Hom.: 688 AF XY: 0.0702 AC XY: 9160 AN XY: 130546

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.0543

Gnomad ASJ exome AF: 0.0814

Gnomad EAS exome AF: 0.0801

Gnomad SAS exome AF: 0.0679

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0718

GnomAD4 exome AF: 0.0635 AC: 92314 AN: 1453192 Hom.: 3165 Cov.: 36 AF XY: 0.0635 AC XY: 45903 AN XY: 723168

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.0551

Gnomad4 ASJ exome AF: 0.0791

Gnomad4 EAS exome AF: 0.0639

Gnomad4 SAS exome AF: 0.0674

Gnomad4 FIN exome AF: 0.0944

Gnomad4 NFE exome AF: 0.0594

Gnomad4 OTH exome AF: 0.0710

GnomAD4 genome AF: 0.111 AC: 11931 AN: 107766 Hom.: 534 Cov.: 30 AF XY: 0.114 AC XY: 5882 AN XY: 51596

Gnomad4 AFR AF: 0.144

Gnomad4 AMR AF: 0.115

Gnomad4 ASJ AF: 0.0949

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.0812

Gnomad4 OTH AF: 0.123

Alfa AF: 0.0674 Hom.: 119

Bravo AF: 0.0812

Asia WGS AF: 0.0700 AC: 241 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 26, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 04, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fibrochondrogenesis 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.7
DANN	Benign	0.80

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: rs71664966; hg19: chr1-103496792; COSMIC: COSV62200042; COSMIC: COSV62200042;