1-103003211-A-T

Variant names:

• chr1-103003211-A-T
• rs12136577
• NM_001854.4:c.1998+4T>A

Variant summary

Our verdict is Benign. The variant received -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 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.0003112
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.211
• Publications: 7 publications found

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]

COL11A1 Gene-Disease associations (from GenCC):

• Marshall syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Stickler syndrome type 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Orphanet, Genomics England PanelApp
• fibrochondrogenesis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal dominant 37

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• fibrochondrogenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive Stickler syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 258440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
COL11A1	NM_001854.4	c.1998+4T>A		splice_region_variant, intron_variant	Intron 21 of 66	ENST00000370096.9	NP_001845.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A1	ENST00000370096.9	c.1998+4T>A		splice_region_variant, intron_variant	Intron 21 of 66	1	NM_001854.4	ENSP00000359114.3

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

GnomAD2 exomes AF: 0.123 AC: 30761 AN: 250108 AF XY: 0.121

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 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

African (AFR) AF: 0.0457 AC: 1531 AN: 33468

American (AMR) AF: 0.181 AC: 8092 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2969 AN: 26102

East Asian (EAS) AF: 0.00244 AC: 97 AN: 39690

South Asian (SAS) AF: 0.0738 AC: 6359 AN: 86180

European-Finnish (FIN) AF: 0.165 AC: 8806 AN: 53348

Middle Eastern (MID) AF: 0.135 AC: 780 AN: 5768

European-Non Finnish (NFE) AF: 0.141 AC: 156799 AN: 1111384

Other (OTH) AF: 0.125 AC: 7517 AN: 60338

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

African (AFR) AF: 0.0477 AC: 1980 AN: 41500

American (AMR) AF: 0.129 AC: 1968 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3464

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5176

South Asian (SAS) AF: 0.0645 AC: 311 AN: 4820

European-Finnish (FIN) AF: 0.161 AC: 1700 AN: 10570

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9615 AN: 67946

Other (OTH) AF: 0.0914 AC: 193 AN: 2112

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Fibrochondrogenesis 1 Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Stickler syndrome type 2 Benign:2

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. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing loss, autosomal dominant 37 Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Marshall syndrome Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	11
DANN	Benign	0.58
PhyloP100		-0.21
Mutation Taster		=39/61	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12136577; hg19: chr1-103468767;