rs12136865

Variant names:

• chr1-103078878-A-G
• rs12136865
• NM_001854.4:c.275-7T>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.275-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,584,692 control chromosomes in the GnomAD database, including 19,380 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 0.14 (1593 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17787 hom.)
• Consequence: COL11A1 NM_001854.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003413
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.36
• 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=-0.78).
• BP6: Variant 1-103078878-A-G is Benign according to our data. Variant chr1-103078878-A-G is described in ClinVar as Benign. ClinVar VariationId is 258452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.157 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.275-7T>C		splice_region intron	N/A	NP_001845.3
	COL11A1	NM_080629.3		c.275-7T>C		splice_region intron	N/A	NP_542196.2
	COL11A1	NM_001190709.2		c.275-7T>C		splice_region 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.275-7T>C		splice_region intron	N/A	ENSP00000359114.3
	COL11A1	ENST00000512756.5	TSL:1	c.275-7T>C		splice_region intron	N/A	ENSP00000426533.1
	COL11A1	ENST00000358392.6	TSL:5	c.275-7T>C		splice_region intron	N/A	ENSP00000351163.2

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20903 AN: 151990 Hom.: 1591 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.00887

Gnomad SAS AF: 0.0907

Gnomad FIN AF: 0.206

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.149 AC: 34605 AN: 232020 AF XY: 0.147

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.143

Gnomad EAS exome AF: 0.00654

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.154 AC: 220279 AN: 1432584 Hom.: 17787 Cov.: 27 AF XY: 0.153 AC XY: 108832 AN XY: 713402

African (AFR) AF: 0.106 AC: 3489 AN: 32812

American (AMR) AF: 0.210 AC: 9091 AN: 43284

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 3664 AN: 25810

East Asian (EAS) AF: 0.00689 AC: 271 AN: 39350

South Asian (SAS) AF: 0.102 AC: 8713 AN: 85056

European-Finnish (FIN) AF: 0.207 AC: 10936 AN: 52884

Middle Eastern (MID) AF: 0.183 AC: 1009 AN: 5510

European-Non Finnish (NFE) AF: 0.160 AC: 174160 AN: 1088650

Other (OTH) AF: 0.151 AC: 8946 AN: 59228

GnomAD4 genome AF: 0.138 AC: 20926 AN: 152108 Hom.: 1593 Cov.: 32 AF XY: 0.138 AC XY: 10274 AN XY: 74352

African (AFR) AF: 0.102 AC: 4251 AN: 41526

American (AMR) AF: 0.153 AC: 2327 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 483 AN: 3468

East Asian (EAS) AF: 0.00889 AC: 46 AN: 5172

South Asian (SAS) AF: 0.0908 AC: 438 AN: 4826

European-Finnish (FIN) AF: 0.206 AC: 2180 AN: 10596

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10820 AN: 67948

Other (OTH) AF: 0.127 AC: 267 AN: 2110

Alfa AF: 0.151 Hom.: 1069

Bravo AF: 0.134

Asia WGS AF: 0.0590 AC: 204 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Fibrochondrogenesis 1 (2)
-	-	2	not provided (2)
-	-	2	Stickler syndrome type 2 (2)
-	-	1	Hearing loss, autosomal dominant 37 (1)
-	-	1	Marshall syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.8
DANN	Benign	0.70
PhyloP100		2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.030
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: rs12136865; hg19: chr1-103544434;