17-50187014-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000088.4(COL1A1):​c.3531+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. 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 splice_donor

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.84
Variant links:
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 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.024345847 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-50187014-C-T is Pathogenic according to our data. Variant chr17-50187014-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 568906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50187014-C-T is described in Lovd as [Pathogenic]. Variant chr17-50187014-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL1A1NM_000088.4 linkuse as main transcriptc.3531+1G>A splice_donor_variant ENST00000225964.10 NP_000079.2
COL1A1XM_005257058.5 linkuse as main transcriptc.3261+1G>A splice_donor_variant XP_005257115.2
COL1A1XM_005257059.5 linkuse as main transcriptc.2613+1G>A splice_donor_variant XP_005257116.2
COL1A1XM_011524341.2 linkuse as main transcriptc.3333+1G>A splice_donor_variant XP_011522643.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL1A1ENST00000225964.10 linkuse as main transcriptc.3531+1G>A splice_donor_variant 1 NM_000088.4 ENSP00000225964 P1
COL1A1ENST00000510710.3 linkuse as main transcriptn.109G>A non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Osteogenesis imperfecta Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenNov 06, 2018- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaNov 19, 2021The COL1A1 c.3531+1G>A variant occurs in a canonical splice site (donor) and is predicted to disrupt the normal gene product. The c.3531+1G>A variant has been reported in a heterozygous state in an individual with osteogenesis imperfecta, type I (Willing et al. 1994). The c.3531+1G>A variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggests the variant is rare. Experimental studies have shown that the variant leads to preservation of the reading frame with skipping of exon 48 and reduced mRNA levels (Willing et al. 1994). Other nucleotides changes at this same position have been reported in at least three individuals with osteogenesis imperfecta (Bardai et al. 2016; Essawi et al. 2018). Based on the collective evidence, the c.3531+1G>A variant is classified as pathogenic for COL1A1-related osteogenesis imperfecta. -
Osteogenesis imperfecta type I Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 14, 2018This sequence change affects a donor splice site in intron 47 of the COL1A1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with osteogenesis imperfecta type I (PMID: 7942841). The variant is also known as a substitution at the 5' donor splice site at position +1 of intron 48. Experimental studies have shown that this splice variant leads to skipping of exon 48 and reduced mRNA levels (PMID: 7942841). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL1A1 are known to be pathogenic (PMID: 7942841, 9295084, 9443882). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.60
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
32
DANN
Uncertain
0.99
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Uncertain
0.97
D
MutationTaster
Benign
1.0
D
GERP RS
3.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.91
SpliceAI score (max)
0.97
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.97
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs72656326; hg19: chr17-48264375; API