rs1903787

Variant names:

• chr1-102978941-A-G
• rs1903787
• NM_001854.4:c.2656-28T>C

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.2656-28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.268 in 1,613,396 control chromosomes in the GnomAD database, including 61,716 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8671 hom., cov: 32)
  • Exomes 𝑓: 0.26 (53045 hom.)
• Consequence: COL11A1 NM_001854.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.507
• Publications: 11 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=-0.91).
• BP6: Variant 1-102978941-A-G is Benign according to our data. Variant chr1-102978941-A-G is described in ClinVar as Benign. ClinVar VariationId is 258449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001854.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A1	NM_001854.4	MANE Select	c.2656-28T>C		intron	N/A	NP_001845.3
	COL11A1	NM_080629.3		c.2692-28T>C		intron	N/A	NP_542196.2
	COL11A1	NM_001190709.2		c.2539-28T>C		intron	N/A	NP_001177638.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A1	ENST00000370096.9	TSL:1 MANE Select	c.2656-28T>C		intron	N/A	ENSP00000359114.3
	COL11A1	ENST00000512756.5	TSL:1	c.2308-28T>C		intron	N/A	ENSP00000426533.1
	COL11A1	ENST00000635193.1	TSL:1	n.1988-28T>C		intron	N/A	ENSP00000489428.1

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48191 AN: 151922 Hom.: 8652 Cov.: 32

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0865

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.282

GnomAD2 exomes AF: 0.257 AC: 64600 AN: 250996 AF XY: 0.249

Gnomad AFR exome AF: 0.508

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.0886

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.263 AC: 384508 AN: 1461356 Hom.: 53045 Cov.: 34 AF XY: 0.260 AC XY: 188862 AN XY: 727002

African (AFR) AF: 0.507 AC: 16967 AN: 33466

American (AMR) AF: 0.277 AC: 12402 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 6040 AN: 26134

East Asian (EAS) AF: 0.0749 AC: 2974 AN: 39692

South Asian (SAS) AF: 0.168 AC: 14501 AN: 86248

European-Finnish (FIN) AF: 0.272 AC: 14511 AN: 53396

Middle Eastern (MID) AF: 0.303 AC: 1749 AN: 5766

European-Non Finnish (NFE) AF: 0.269 AC: 299272 AN: 1111586

Other (OTH) AF: 0.267 AC: 16092 AN: 60374

GnomAD4 genome AF: 0.317 AC: 48263 AN: 152040 Hom.: 8671 Cov.: 32 AF XY: 0.313 AC XY: 23296 AN XY: 74314

African (AFR) AF: 0.500 AC: 20714 AN: 41458

American (AMR) AF: 0.263 AC: 4014 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 769 AN: 3472

East Asian (EAS) AF: 0.0865 AC: 448 AN: 5178

South Asian (SAS) AF: 0.162 AC: 780 AN: 4822

European-Finnish (FIN) AF: 0.271 AC: 2867 AN: 10586

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17878 AN: 67940

Other (OTH) AF: 0.281 AC: 594 AN: 2116

Alfa AF: 0.283 Hom.: 8702

Bravo AF: 0.326

Asia WGS AF: 0.174 AC: 605 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Fibrochondrogenesis 1 (1)
-	-	1	Hearing loss, autosomal dominant 37 (1)
-	-	1	Marshall syndrome (1)
-	-	1	not specified (1)
-	-	1	Stickler syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.38
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		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: rs1903787; hg19: chr1-103444497;