rs376244140
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_000088.4(COL1A1):c.1929+4A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
COL1A1
NM_000088.4 splice_donor_region, intron
NM_000088.4 splice_donor_region, intron
Scores
1
1
Splicing: ADA: 0.9774
2
Clinical Significance
Conservation
PhyloP100: 3.41
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 Likely_benign. Variant got -3 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
BS2
?
High AC in GnomAd at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.1929+4A>C | splice_donor_region_variant, intron_variant | ENST00000225964.10 | |||
COL1A1 | XM_005257058.5 | c.1929+4A>C | splice_donor_region_variant, intron_variant | ||||
COL1A1 | XM_005257059.5 | c.1011+4A>C | splice_donor_region_variant, intron_variant | ||||
COL1A1 | XM_011524341.2 | c.1731+4A>C | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.1929+4A>C | splice_donor_region_variant, intron_variant | 1 | NM_000088.4 | P1 | |||
COL1A1 | ENST00000476387.1 | n.278+4A>C | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152190Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251428Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135902
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461890Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9AN XY: 727246
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 27, 2016 | - - |
Osteogenesis imperfecta type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change falls in intron 28 of the COL1A1 gene. It does not directly change the encoded amino acid sequence of the COL1A1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs376244140, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with COL1A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 447139). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
Splicing
Name
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -28
Find out detailed SpliceAI scores and Pangolin per-transcript scores at