rs3753841

Variant names:

• chr1-102914362-G-A
• rs3753841
• NM_001854.4:c.3968C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-102914362-G-A
• chr1-102914362-G-C
• chr1-102914362-G-T

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.3968C>T​(p.Pro1323Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.596 in 1,602,454 control chromosomes in the GnomAD database, including 294,801 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1323T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.50 (22450 hom., cov: 31)
  • Exomes 𝑓: 0.61 (272351 hom.)
• Consequence: COL11A1 NM_001854.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 9.29
• Publications: 129 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 (MetaRNN=5.535358E-5).
• BP6: Variant 1-102914362-G-A is Benign according to our data. Variant chr1-102914362-G-A is described in ClinVar as Benign. ClinVar VariationId is 258461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.681 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.3968C>T	p.Pro1323Leu	missense	Exon 52 of 67	NP_001845.3
	COL11A1	NM_080629.3		c.4004C>T	p.Pro1335Leu	missense	Exon 52 of 67	NP_542196.2	P12107-2
	COL11A1	NM_001190709.2		c.3851C>T	p.Pro1284Leu	missense	Exon 51 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.3968C>T	p.Pro1323Leu	missense	Exon 52 of 67	ENSP00000359114.3	P12107-1
	COL11A1	ENST00000512756.5	TSL:1	c.3620C>T	p.Pro1207Leu	missense	Exon 50 of 65	ENSP00000426533.1	P12107-4
	COL11A1	ENST00000635193.1	TSL:1	n.*1218C>T		non_coding_transcript_exon	Exon 49 of 64	ENSP00000489428.1	A0A0U1RRA7

Frequencies

GnomAD3 genomes AF: 0.497 AC: 75315 AN: 151610 Hom.: 22440 Cov.: 31

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.628

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.700

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.537

GnomAD2 exomes AF: 0.605 AC: 150972 AN: 249372 AF XY: 0.609

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.594

Gnomad EAS exome AF: 0.683

Gnomad FIN exome AF: 0.667

Gnomad NFE exome AF: 0.611

Gnomad OTH exome AF: 0.627

GnomAD4 exome AF: 0.606 AC: 879585 AN: 1450726 Hom.: 272351 Cov.: 33 AF XY: 0.608 AC XY: 438568 AN XY: 721758

African (AFR) AF: 0.115 AC: 3837 AN: 33396

American (AMR) AF: 0.738 AC: 32838 AN: 44522

Ashkenazi Jewish (ASJ) AF: 0.594 AC: 15476 AN: 26038

East Asian (EAS) AF: 0.674 AC: 26671 AN: 39570

South Asian (SAS) AF: 0.592 AC: 50200 AN: 84744

European-Finnish (FIN) AF: 0.665 AC: 35343 AN: 53146

Middle Eastern (MID) AF: 0.581 AC: 3337 AN: 5748

European-Non Finnish (NFE) AF: 0.613 AC: 676162 AN: 1103586

Other (OTH) AF: 0.596 AC: 35721 AN: 59976

GnomAD4 genome AF: 0.496 AC: 75330 AN: 151728 Hom.: 22450 Cov.: 31 AF XY: 0.504 AC XY: 37348 AN XY: 74154

African (AFR) AF: 0.135 AC: 5599 AN: 41342

American (AMR) AF: 0.673 AC: 10253 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 2110 AN: 3468

East Asian (EAS) AF: 0.700 AC: 3609 AN: 5156

South Asian (SAS) AF: 0.589 AC: 2834 AN: 4812

European-Finnish (FIN) AF: 0.657 AC: 6894 AN: 10492

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42148 AN: 67914

Other (OTH) AF: 0.541 AC: 1138 AN: 2104

Alfa AF: 0.584 Hom.: 129819

Bravo AF: 0.484

TwinsUK AF: 0.595 AC: 2206

ALSPAC AF: 0.618 AC: 2381

ESP6500AA AF: 0.140 AC: 615

ESP6500EA AF: 0.612 AC: 5260

ExAC AF: 0.590 AC: 71557

Asia WGS AF: 0.605 AC: 2101 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Fibrochondrogenesis 1 (3)
-	-	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
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.000055	T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.60
Sift	Benign	0.042	D
Sift4G	Benign	0.087	T
Polyphen		0.044	B
Vest4		0.34
MPC		0.12
ClinPred		0.058	T
GERP RS		5.8
Varity_R		0.32
gMVP		0.32
Mutation Taster		=97/3	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: rs3753841; hg19: chr1-103379918; COSMIC: COSV62176478;