rs2229783

Positions:

• chr1-102886895-A-C
• chr1-102886895-A-G
• chr1-102886895-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001854.4(COL11A1):​c.4770T>G​(p.Ile1590Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I1590I) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: COL11A1 NM_001854.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.790

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL11A1	NM_001854.4	c.4770T>G	p.Ile1590Met	missense_variant	63/67	ENST00000370096.9	NP_001845.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL11A1	ENST00000370096.9	c.4770T>G	p.Ile1590Met	missense_variant	63/67	1	NM_001854.4	ENSP00000359114	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151872 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 52

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74148

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	1.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Uncertain	2.9	M;.;.;.
MutationTaster	Benign	0.00021	P;P;P;P
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.79
MutPred		0.56		Gain of disorder (P = 0.0205);.;.;.;
MVP		0.78
MPC		0.12
ClinPred		0.98	D
GERP RS		-5.2
Varity_R		0.43
gMVP		0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229783; hg19: chr1-103352451;