1-103025905-T-G

Variant names:

• chr1-103025905-T-G
• rs12731843
• NM_001854.4:c.898-292A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_080629.3(COL11A1):​c.828A>C​(p.Lys276Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0653 in 1,612,598 control chromosomes in the GnomAD database, including 3,701 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (532 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3169 hom.)
• Consequence: COL11A1 NM_080629.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0480
• Publications: 18 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=0.0017307997).
• BP6: Variant 1-103025905-T-G is Benign according to our data. Variant chr1-103025905-T-G is described in ClinVar as Benign. ClinVar VariationId is 668356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080629.3. 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.898-292A>C		intron	N/A	NP_001845.3
	COL11A1	NM_080629.3		c.828A>C	p.Lys276Asn	missense	Exon 6 of 67	NP_542196.2
	COL11A1	NM_001190709.2		c.781-292A>C		intron	N/A	NP_001177638.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL11A1	ENST00000370096.9	TSL:1 MANE Select	c.898-292A>C		intron	N/A	ENSP00000359114.3
	COL11A1	ENST00000512756.5	TSL:1	c.897+311A>C		intron	N/A	ENSP00000426533.1
	COL11A1	ENST00000635193.1	TSL:1	n.214-292A>C		intron	N/A	ENSP00000489428.1

Frequencies

GnomAD3 genomes AF: 0.0789 AC: 12002 AN: 152066 Hom.: 529 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0658

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.0724

Gnomad SAS AF: 0.0723

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0591

Gnomad OTH AF: 0.0794

GnomAD2 exomes AF: 0.0706 AC: 17714 AN: 250762 AF XY: 0.0704

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0546

Gnomad ASJ exome AF: 0.0821

Gnomad EAS exome AF: 0.0798

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.0615

Gnomad OTH exome AF: 0.0708

GnomAD4 exome AF: 0.0638 AC: 93242 AN: 1460414 Hom.: 3169 Cov.: 31 AF XY: 0.0638 AC XY: 46379 AN XY: 726624

African (AFR) AF: 0.121 AC: 4064 AN: 33452

American (AMR) AF: 0.0556 AC: 2486 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0796 AC: 2079 AN: 26128

East Asian (EAS) AF: 0.0641 AC: 2543 AN: 39672

South Asian (SAS) AF: 0.0679 AC: 5852 AN: 86248

European-Finnish (FIN) AF: 0.0990 AC: 5225 AN: 52800

Middle Eastern (MID) AF: 0.0944 AC: 544 AN: 5760

European-Non Finnish (NFE) AF: 0.0596 AC: 66185 AN: 1111294

Other (OTH) AF: 0.0706 AC: 4264 AN: 60354

GnomAD4 genome AF: 0.0791 AC: 12033 AN: 152184 Hom.: 532 Cov.: 32 AF XY: 0.0804 AC XY: 5982 AN XY: 74422

African (AFR) AF: 0.114 AC: 4718 AN: 41520

American (AMR) AF: 0.0658 AC: 1004 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 253 AN: 3470

East Asian (EAS) AF: 0.0725 AC: 375 AN: 5170

South Asian (SAS) AF: 0.0726 AC: 350 AN: 4824

European-Finnish (FIN) AF: 0.104 AC: 1099 AN: 10606

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0591 AC: 4020 AN: 68008

Other (OTH) AF: 0.0791 AC: 167 AN: 2112

Alfa AF: 0.0661 Hom.: 1006

Bravo AF: 0.0793

TwinsUK AF: 0.0547 AC: 203

ALSPAC AF: 0.0586 AC: 226

ESP6500AA AF: 0.112 AC: 493

ESP6500EA AF: 0.0636 AC: 547

ExAC AF: 0.0711 AC: 8635

Asia WGS AF: 0.0680 AC: 237 AN: 3478

EpiCase AF: 0.0643

EpiControl AF: 0.0634

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.95
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.048
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.094
Sift	Benign	0.45	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.044
MutPred		0.34		Loss of methylation at K276 (P = 6e-04)
ClinPred		0.0097	T
GERP RS		0.88
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: rs12731843; hg19: chr1-103491461; COSMIC: COSV62181630; COSMIC: COSV62181630;