1-102876836-T-C

Variant names:

• chr1-102876836-T-C
• rs9659030
• NM_001854.4:c.*1183A>G

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.*1183A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 152,138 control chromosomes in the GnomAD database, including 3,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3063 hom., cov: 32)
  • Exomes 𝑓: 0.22 (5 hom.)
• Consequence: COL11A1 NM_001854.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.29
• Publications: 20 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=-0.55).
• BP6: Variant 1-102876836-T-C is Benign according to our data. Variant chr1-102876836-T-C is described in ClinVar as Benign. ClinVar VariationId is 291477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL11A1	NM_001854.4	c.*1183A>G		3_prime_UTR_variant	Exon 67 of 67	ENST00000370096.9	NP_001845.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL11A1	ENST00000370096.9	c.*1183A>G		3_prime_UTR_variant	Exon 67 of 67	1	NM_001854.4	ENSP00000359114.3
COL11A1	ENST00000358392.6	c.*1183A>G		3_prime_UTR_variant	Exon 67 of 67	5		ENSP00000351163.2
COL11A1	ENST00000353414.8	c.*1183A>G		3_prime_UTR_variant	Exon 66 of 66	5		ENSP00000302551.6

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29742 AN: 151870 Hom.: 3066 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.192

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.251

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.148

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.174

GnomAD4 exome AF: 0.220 AC: 33 AN: 150 Hom.: 5 Cov.: 0 AF XY: 0.222 AC XY: 20 AN XY: 90

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.219 AC: 32 AN: 146

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.196 AC: 29753 AN: 151988 Hom.: 3063 Cov.: 32 AF XY: 0.194 AC XY: 14444 AN XY: 74316

African (AFR) AF: 0.175 AC: 7269 AN: 41514

American (AMR) AF: 0.192 AC: 2919 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 421 AN: 3472

East Asian (EAS) AF: 0.251 AC: 1295 AN: 5168

South Asian (SAS) AF: 0.299 AC: 1441 AN: 4820

European-Finnish (FIN) AF: 0.137 AC: 1447 AN: 10590

Middle Eastern (MID) AF: 0.145 AC: 41 AN: 282

European-Non Finnish (NFE) AF: 0.213 AC: 14484 AN: 67884

Other (OTH) AF: 0.172 AC: 363 AN: 2112

Alfa AF: 0.208 Hom.: 7652

Bravo AF: 0.197

Asia WGS AF: 0.258 AC: 887 AN: 3444

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 10, 2021

GeneDx

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

- -

Fibrochondrogenesis 1 Benign:1

Jan 12, 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 12, 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	-0.55
CADD	Benign	5.8
DANN	Benign	0.70
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9659030; hg19: chr1-103342392;