NM_001854.4:c.4603T>C

Variant names:

• chr1-102888582-A-G
• rs1676486
• NM_001854.4:c.4603T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001854.4(COL11A1):​c.4603T>C​(p.Ser1535Pro) variant causes a missense change. The variant allele was found at a frequency of 0.802 in 1,612,246 control chromosomes in the GnomAD database, including 519,995 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1535L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.81 (50267 hom., cov: 32)
  • Exomes 𝑓: 0.80 (469728 hom.)
• Consequence: COL11A1 NM_001854.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 5.47
• Publications: 79 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 8 uncertain in NM_001854.4
• BP4: Computational evidence support a benign effect (MetaRNN=1.2520567E-6).
• BP6: Variant 1-102888582-A-G is Benign according to our data. Variant chr1-102888582-A-G is described in ClinVar as Benign. ClinVar VariationId is 17137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.855 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.4603T>C	p.Ser1535Pro	missense	Exon 62 of 67	NP_001845.3
	COL11A1	NM_080629.3		c.4639T>C	p.Ser1547Pro	missense	Exon 62 of 67	NP_542196.2	P12107-2
	COL11A1	NM_001190709.2		c.4486T>C	p.Ser1496Pro	missense	Exon 61 of 66	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.4603T>C	p.Ser1535Pro	missense	Exon 62 of 67	ENSP00000359114.3	P12107-1
	COL11A1	ENST00000512756.5	TSL:1	c.4255T>C	p.Ser1419Pro	missense	Exon 60 of 65	ENSP00000426533.1	P12107-4
	COL11A1	ENST00000635193.1	TSL:1	n.*1853T>C		non_coding_transcript_exon	Exon 59 of 64	ENSP00000489428.1	A0A0U1RRA7

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123471 AN: 152046 Hom.: 50220 Cov.: 32

Gnomad AFR AF: 0.805

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.868

Gnomad ASJ AF: 0.825

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.810

Gnomad OTH AF: 0.830

GnomAD2 exomes AF: 0.799 AC: 200324 AN: 250612 AF XY: 0.792

Gnomad AFR exome AF: 0.807

Gnomad AMR exome AF: 0.873

Gnomad ASJ exome AF: 0.820

Gnomad EAS exome AF: 0.726

Gnomad FIN exome AF: 0.861

Gnomad NFE exome AF: 0.808

Gnomad OTH exome AF: 0.817

GnomAD4 exome AF: 0.801 AC: 1169051 AN: 1460082 Hom.: 469728 Cov.: 42 AF XY: 0.797 AC XY: 578837 AN XY: 726364

African (AFR) AF: 0.802 AC: 26825 AN: 33428

American (AMR) AF: 0.874 AC: 39019 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.820 AC: 21415 AN: 26110

East Asian (EAS) AF: 0.704 AC: 27930 AN: 39668

South Asian (SAS) AF: 0.674 AC: 58147 AN: 86234

European-Finnish (FIN) AF: 0.856 AC: 45683 AN: 53390

Middle Eastern (MID) AF: 0.812 AC: 4680 AN: 5762

European-Non Finnish (NFE) AF: 0.808 AC: 896866 AN: 1110484

Other (OTH) AF: 0.804 AC: 48486 AN: 60338

GnomAD4 genome AF: 0.812 AC: 123577 AN: 152164 Hom.: 50267 Cov.: 32 AF XY: 0.813 AC XY: 60462 AN XY: 74380

African (AFR) AF: 0.805 AC: 33409 AN: 41518

American (AMR) AF: 0.868 AC: 13246 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 2862 AN: 3470

East Asian (EAS) AF: 0.749 AC: 3870 AN: 5164

South Asian (SAS) AF: 0.665 AC: 3209 AN: 4824

European-Finnish (FIN) AF: 0.865 AC: 9176 AN: 10604

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.810 AC: 55065 AN: 68002

Other (OTH) AF: 0.832 AC: 1759 AN: 2114

Alfa AF: 0.813 Hom.: 88485

Bravo AF: 0.818

TwinsUK AF: 0.794 AC: 2946

ALSPAC AF: 0.809 AC: 3116

ESP6500AA AF: 0.799 AC: 3519

ESP6500EA AF: 0.811 AC: 6977

ExAC AF: 0.794 AC: 96377

Asia WGS AF: 0.737 AC: 2563 AN: 3478

EpiCase AF: 0.810

EpiControl AF: 0.814

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Fibrochondrogenesis 1 (3)
-	-	2	not provided (2)
-	-	2	Stickler syndrome type 2 (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Hearing loss, autosomal dominant 37 (1)
-	-	1	Marshall syndrome (1)
-	-	-	Lumbar disk herniation, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.67
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.053	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-1.4	N
PhyloP100		5.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	5.0	N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.15
ClinPred		0.014	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs1676486; hg19: chr1-103354138; COSMIC: COSV62176458; COSMIC: COSV62176458;