chr1-103002739-C-T

Variant names:

• chr1-103002739-C-T
• rs2622875
• NM_001854.4:c.2043+8G>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.2043+8G>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 0.0263 in 1,609,480 control chromosomes in the GnomAD database, including 878 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 0.044 (253 hom., cov: 32)
  • Exomes 𝑓: 0.024 (625 hom.)
• Consequence: COL11A1 NM_001854.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002870
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.19
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P
• Stickler syndrome type 2

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• 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 nonsyndromic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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=-0.74).
• BP6: Variant 1-103002739-C-T is Benign according to our data. Variant chr1-103002739-C-T is described in ClinVar as Benign. ClinVar VariationId is 258442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.095 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A1	NM_001854.4	MANE Select	c.2043+8G>A		splice_region intron	N/A	NP_001845.3
	COL11A1	NM_080629.3		c.2079+8G>A		splice_region intron	N/A	NP_542196.2	P12107-2
	COL11A1	NM_001190709.2		c.1926+8G>A		splice_region intron	N/A	NP_001177638.1	P12107-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A1	ENST00000370096.9	TSL:1 MANE Select	c.2043+8G>A		splice_region intron	N/A	ENSP00000359114.3	P12107-1
	COL11A1	ENST00000512756.5	TSL:1	c.1695+8G>A		splice_region intron	N/A	ENSP00000426533.1	P12107-4
	COL11A1	ENST00000635193.1	TSL:1	n.1359+8G>A		splice_region intron	N/A	ENSP00000489428.1	A0A0U1RRA7

Frequencies

GnomAD3 genomes AF: 0.0440 AC: 6696 AN: 152022 Hom.: 251 Cov.: 32

Gnomad AFR AF: 0.0972

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.00579

Gnomad SAS AF: 0.0182

Gnomad FIN AF: 0.0466

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0461

GnomAD2 exomes AF: 0.0294 AC: 7378 AN: 251116 AF XY: 0.0274

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.00490

Gnomad FIN exome AF: 0.0432

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.0307

GnomAD4 exome AF: 0.0244 AC: 35570 AN: 1457340 Hom.: 625 Cov.: 30 AF XY: 0.0238 AC XY: 17263 AN XY: 725366

African (AFR) AF: 0.104 AC: 3479 AN: 33292

American (AMR) AF: 0.0350 AC: 1565 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0286 AC: 747 AN: 26080

East Asian (EAS) AF: 0.00451 AC: 179 AN: 39656

South Asian (SAS) AF: 0.0188 AC: 1617 AN: 86172

European-Finnish (FIN) AF: 0.0426 AC: 2276 AN: 53410

Middle Eastern (MID) AF: 0.0579 AC: 333 AN: 5748

European-Non Finnish (NFE) AF: 0.0212 AC: 23470 AN: 1108094

Other (OTH) AF: 0.0316 AC: 1904 AN: 60228

GnomAD4 genome AF: 0.0442 AC: 6717 AN: 152140 Hom.: 253 Cov.: 32 AF XY: 0.0448 AC XY: 3331 AN XY: 74360

African (AFR) AF: 0.0975 AC: 4046 AN: 41502

American (AMR) AF: 0.0311 AC: 475 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 88 AN: 3470

East Asian (EAS) AF: 0.00580 AC: 30 AN: 5170

South Asian (SAS) AF: 0.0185 AC: 89 AN: 4822

European-Finnish (FIN) AF: 0.0466 AC: 494 AN: 10592

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0202 AC: 1376 AN: 68006

Other (OTH) AF: 0.0451 AC: 95 AN: 2106

Alfa AF: 0.0319 Hom.: 74

Bravo AF: 0.0474

Asia WGS AF: 0.0260 AC: 89 AN: 3478

EpiCase AF: 0.0246

EpiControl AF: 0.0225

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Connective tissue disorder (1)
-	-	1	Fibrochondrogenesis 1 (1)
-	-	1	Stickler syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.93
DANN	Benign	0.57
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.010
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: rs2622875; hg19: chr1-103468295;