chr17-50186507-C-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000088.4(COL1A1):c.3815G>T(p.Gly1272Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
COL1A1
NM_000088.4 missense, splice_region
NM_000088.4 missense, splice_region
Scores
12
3
1
Splicing: ADA: 0.9985
2
Clinical Significance
Conservation
PhyloP100: 6.12
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 17 ACMG points.
PM1
In a disulfide_bond (size 32) in uniprot entity CO1A1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_000088.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A1. . Gene score misZ 3.5319 (greater than the threshold 3.09). Trascript score misZ 5.7733 (greater than threshold 3.09). GenCC has associacion of gene with Caffey disease, Ehlers-Danlos/osteogenesis imperfecta syndrome, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, 1, high bone mass osteogenesis imperfecta, osteogenesis imperfecta type 4, Ehlers-Danlos syndrome, classic type, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 17-50186507-C-A is Pathogenic according to our data. Variant chr17-50186507-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 425626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50186507-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.3815G>T | p.Gly1272Val | missense_variant, splice_region_variant | 49/51 | ENST00000225964.10 | NP_000079.2 | |
COL1A1 | XM_011524341.2 | c.3617G>T | p.Gly1206Val | missense_variant, splice_region_variant | 46/48 | XP_011522643.1 | ||
COL1A1 | XM_005257058.5 | c.3545G>T | p.Gly1182Val | missense_variant, splice_region_variant | 47/49 | XP_005257115.2 | ||
COL1A1 | XM_005257059.5 | c.2897G>T | p.Gly966Val | missense_variant, splice_region_variant | 36/38 | XP_005257116.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.3815G>T | p.Gly1272Val | missense_variant, splice_region_variant | 49/51 | 1 | NM_000088.4 | ENSP00000225964.6 | ||
COL1A1 | ENST00000510710.3 | n.484G>T | splice_region_variant, non_coding_transcript_exon_variant | 2/2 | 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/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Osteogenesis imperfecta type I Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 25, 2020 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has been observed in individuals with osteogenesis imperfecta type I or IV (PMID: 25146735, 31414283, 25944380, 27510842). ClinVar contains an entry for this variant (Variation ID: 425626). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 1272 of the COL1A1 protein (p.Gly1272Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Medical Sciences, Uppsala University | - | - - |
Osteogenesis imperfecta with normal sclerae, dominant form Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Medical Sciences, Uppsala University | - | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 02, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25146735, 27510842, 31414283, 25944380) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Vest4
MutPred
Loss of ubiquitination at K1270 (P = 0.0597);
MVP
MPC
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at