rs55821405

Variant names:

• chr1-102889503-G-T
• rs55821405
• NM_001854.4:c.4416C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001854.4(COL11A1):​c.4416C>A​(p.Asp1472Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00334 in 1,613,130 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (19 hom.)
• Consequence: COL11A1 NM_001854.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.54
• Publications: 8 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=0.014775157).
• BP6: Variant 1-102889503-G-T is Benign according to our data. Variant chr1-102889503-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0029 (439/151560) while in subpopulation AMR AF = 0.0037 (56/15154). AF 95% confidence interval is 0.00311. There are 2 homozygotes in GnomAd4. There are 204 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.4416C>A	p.Asp1472Glu	missense	Exon 59 of 67	NP_001845.3
	COL11A1	NM_080629.3		c.4452C>A	p.Asp1484Glu	missense	Exon 59 of 67	NP_542196.2
	COL11A1	NM_001190709.2		c.4299C>A	p.Asp1433Glu	missense	Exon 58 of 66	NP_001177638.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A1	ENST00000370096.9	TSL:1 MANE Select	c.4416C>A	p.Asp1472Glu	missense	Exon 59 of 67	ENSP00000359114.3
	COL11A1	ENST00000512756.5	TSL:1	c.4068C>A	p.Asp1356Glu	missense	Exon 57 of 65	ENSP00000426533.1
	COL11A1	ENST00000635193.1	TSL:1	n.*1666C>A		non_coding_transcript_exon	Exon 56 of 64	ENSP00000489428.1

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 439 AN: 151440 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000534

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.00370

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00312

Gnomad FIN AF: 0.00134

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.00289

GnomAD2 exomes AF: 0.00337 AC: 848 AN: 251434 AF XY: 0.00350

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00339 AC: 4951 AN: 1461570 Hom.: 19 Cov.: 32 AF XY: 0.00356 AC XY: 2592 AN XY: 727088

African (AFR) AF: 0.000628 AC: 21 AN: 33466

American (AMR) AF: 0.00253 AC: 113 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 471 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39672

South Asian (SAS) AF: 0.00323 AC: 279 AN: 86250

European-Finnish (FIN) AF: 0.00163 AC: 87 AN: 53416

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5762

European-Non Finnish (NFE) AF: 0.00334 AC: 3711 AN: 1111794

Other (OTH) AF: 0.00407 AC: 246 AN: 60384

GnomAD4 genome AF: 0.00290 AC: 439 AN: 151560 Hom.: 2 Cov.: 31 AF XY: 0.00275 AC XY: 204 AN XY: 74062

African (AFR) AF: 0.000532 AC: 22 AN: 41342

American (AMR) AF: 0.00370 AC: 56 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00313 AC: 15 AN: 4796

European-Finnish (FIN) AF: 0.00134 AC: 14 AN: 10480

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00348 AC: 236 AN: 67890

Other (OTH) AF: 0.00286 AC: 6 AN: 2100

Alfa AF: 0.00376 Hom.: 7

Bravo AF: 0.00306

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00450

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	COL11A1-related disorder (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Fibrochondrogenesis 1 (1)
-	-	1	not specified (1)
-	-	1	Stickler syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	-0.75	N
PhyloP100		2.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.55
Sift	Benign	0.15	T
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.69
MutPred		0.28		Loss of methylation at R1473 (P = 0.1799)
MVP		0.91
MPC		0.11
ClinPred		0.023	T
GERP RS		4.5
Varity_R		0.32
gMVP		0.14
Mutation Taster		=92/8	polymorphism

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: rs55821405; hg19: chr1-103355059; COSMIC: COSV62172603; COSMIC: COSV62172603;