rs11164663

Variant names:

• chr1-103082941-A-C
• rs11164663
• NM_001854.4:c.138T>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.138T>G​(p.Asp46Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0758 in 1,612,862 control chromosomes in the GnomAD database, including 5,153 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.083 (599 hom., cov: 31)
  • Exomes 𝑓: 0.075 (4554 hom.)
• Consequence: COL11A1 NM_001854.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.13
• Publications: 22 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 (MetaRNN=0.0025791824).
• BP6: Variant 1-103082941-A-C is Benign according to our data. Variant chr1-103082941-A-C is described in ClinVar as Benign. ClinVar VariationId is 258438.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 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.138T>G	p.Asp46Glu	missense	Exon 2 of 67	NP_001845.3
	COL11A1	NM_080629.3		c.138T>G	p.Asp46Glu	missense	Exon 2 of 67	NP_542196.2
	COL11A1	NM_001190709.2		c.138T>G	p.Asp46Glu	missense	Exon 2 of 66	NP_001177638.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A1	ENST00000370096.9	TSL:1 MANE Select	c.138T>G	p.Asp46Glu	missense	Exon 2 of 67	ENSP00000359114.3
	COL11A1	ENST00000512756.5	TSL:1	c.138T>G	p.Asp46Glu	missense	Exon 2 of 65	ENSP00000426533.1
	COL11A1	ENST00000358392.6	TSL:5	c.138T>G	p.Asp46Glu	missense	Exon 2 of 67	ENSP00000351163.2

Frequencies

GnomAD3 genomes AF: 0.0833 AC: 12658 AN: 151946 Hom.: 598 Cov.: 31

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0552

Gnomad ASJ AF: 0.0528

Gnomad EAS AF: 0.0120

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0616

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0781

Gnomad OTH AF: 0.0783

GnomAD2 exomes AF: 0.0612 AC: 15343 AN: 250700 AF XY: 0.0589

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0539

Gnomad EAS exome AF: 0.00865

Gnomad FIN exome AF: 0.0609

Gnomad NFE exome AF: 0.0787

Gnomad OTH exome AF: 0.0614

GnomAD4 exome AF: 0.0750 AC: 109519 AN: 1460798 Hom.: 4554 Cov.: 32 AF XY: 0.0730 AC XY: 53054 AN XY: 726686

African (AFR) AF: 0.133 AC: 4460 AN: 33426

American (AMR) AF: 0.0354 AC: 1582 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 1459 AN: 26086

East Asian (EAS) AF: 0.00885 AC: 351 AN: 39650

South Asian (SAS) AF: 0.0250 AC: 2155 AN: 86102

European-Finnish (FIN) AF: 0.0610 AC: 3254 AN: 53376

Middle Eastern (MID) AF: 0.0533 AC: 307 AN: 5762

European-Non Finnish (NFE) AF: 0.0825 AC: 91706 AN: 1111394

Other (OTH) AF: 0.0704 AC: 4245 AN: 60338

GnomAD4 genome AF: 0.0833 AC: 12672 AN: 152064 Hom.: 599 Cov.: 31 AF XY: 0.0818 AC XY: 6083 AN XY: 74360

African (AFR) AF: 0.128 AC: 5311 AN: 41472

American (AMR) AF: 0.0551 AC: 841 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0528 AC: 183 AN: 3468

East Asian (EAS) AF: 0.0118 AC: 61 AN: 5172

South Asian (SAS) AF: 0.0218 AC: 105 AN: 4822

European-Finnish (FIN) AF: 0.0616 AC: 653 AN: 10604

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0781 AC: 5310 AN: 67952

Other (OTH) AF: 0.0789 AC: 166 AN: 2104

Alfa AF: 0.0790 Hom.: 2240

Bravo AF: 0.0856

TwinsUK AF: 0.0863 AC: 320

ALSPAC AF: 0.0851 AC: 328

ESP6500AA AF: 0.132 AC: 580

ESP6500EA AF: 0.0820 AC: 705

ExAC AF: 0.0635 AC: 7703

Asia WGS AF: 0.0460 AC: 160 AN: 3476

EpiCase AF: 0.0731

EpiControl AF: 0.0718

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	20
DANN	Benign	0.71
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.41	N
PhyloP100		1.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.13
Sift	Benign	0.74	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.083
MutPred		0.28		Gain of helix (P = 0.0696)
MPC		0.31
ClinPred		0.019	T
GERP RS		3.0
PromoterAI		0.073	Neutral
Varity_R		0.038
gMVP		0.18
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: rs11164663; hg19: chr1-103548497;