rs66523073
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Moderate
The NM_000088.4(COL1A1):c.3064G>A(p.Gly1022Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1022C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
COL1A1
NM_000088.4 missense
NM_000088.4 missense
Scores
11
4
1
Clinical Significance
Conservation
PhyloP100: 4.99
Genes affected
COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
?
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_000088.4
PM2
?
Very rare variant in population databases, with high coverage;
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr17-50188776-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 499457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
?
Missense variant where missense usually causes diseases, COL1A1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
?
Variant 17-50188777-C-T is Pathogenic according to our data. Variant chr17-50188777-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17296.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-50188777-C-T is described in Lovd as [Pathogenic]. Variant chr17-50188777-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.3064G>A | p.Gly1022Ser | missense_variant | 42/51 | ENST00000225964.10 | |
COL1A1 | XM_011524341.2 | c.2866G>A | p.Gly956Ser | missense_variant | 39/48 | ||
COL1A1 | XM_005257058.5 | c.2794G>A | p.Gly932Ser | missense_variant | 40/49 | ||
COL1A1 | XM_005257059.5 | c.2146G>A | p.Gly716Ser | missense_variant | 29/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.3064G>A | p.Gly1022Ser | missense_variant | 42/51 | 1 | NM_000088.4 | P1 | |
COL1A1 | ENST00000511732.1 | n.8G>A | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type III Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 25, 1989 | - - |
COL1A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 07, 2023 | The COL1A1 c.3064G>A variant is predicted to result in the amino acid substitution p.Gly1022Ser. This variant has been reported in several individuals with osteogenesis imperfecta (Reported as Gly844Ser in Pack et al 1989. PubMed ID: 2511192; Chen CP et al 2012. PubMed ID: 23072183; Supp. Table 1, Patient PUMC-208 in Li L et al 2019. PubMed ID: 30715774). This variant is located in the conserved Gly-Xaa-Yaa triple helical domain where substitutions of a glycine are usually pathogenic (Residues 179-1192, https://www.uniprot.org/; Legacy nomenclature in Marini et al. 2007. PubMed ID: 17078022 indicates amino acids 1-1012; Symoens. 2014. PubMed ID: 25146735). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Vest4
MutPred
Gain of phosphorylation at G1022 (P = 0.0039);
MVP
MPC
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at