rs375914028
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Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2
The ENST00000225964.10(COL1A1):c.1005T>A(p.Gly335=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000365 in 1,595,500 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00037 ( 11 hom. )
Consequence
COL1A1
ENST00000225964.10 splice_region, synonymous
ENST00000225964.10 splice_region, synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.195
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 Benign. Variant got -14 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.47).
BP6
Variant 17-50195974-A-T is Benign according to our data. Variant chr17-50195974-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281322.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=2, Likely_benign=4}.
BP7
Synonymous conserved (PhyloP=0.195 with no splicing effect.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000371 (535/1443460) while in subpopulation MID AF= 0.0106 (61/5748). AF 95% confidence interval is 0.00848. There are 11 homozygotes in gnomad4_exome. There are 355 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High AC in GnomAd4 at 48 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| COL1A1 | NM_000088.4 | c.1005T>A | p.Gly335= | splice_region_variant, synonymous_variant | 16/51 | ENST00000225964.10 | NP_000079.2 | |
| COL1A1 | XM_005257058.5 | c.1005T>A | p.Gly335= | splice_region_variant, synonymous_variant | 16/49 | XP_005257115.2 | ||
| COL1A1 | XM_005257059.5 | c.957+340T>A | intron_variant | XP_005257116.2 | ||||
| COL1A1 | XM_011524341.2 | c.957+340T>A | intron_variant | XP_011522643.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| COL1A1 | ENST00000225964.10 | c.1005T>A | p.Gly335= | splice_region_variant, synonymous_variant | 16/51 | 1 | NM_000088.4 | ENSP00000225964 | P1 |
Frequencies
GnomAD3 genomes 0.000316 AC: 48AN: 151922Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000592 AC: 128AN: 216382Hom.: 1 AF XY: 0.000836 AC XY: 97AN XY: 116042
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GnomAD4 exome AF: 0.000371 AC: 535AN: 1443460Hom.: 11 Cov.: 34 AF XY: 0.000496 AC XY: 355AN XY: 716064
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GnomAD4 genome 0.000316 AC: 48AN: 152040Hom.: 0 Cov.: 32 AF XY: 0.000404 AC XY: 30AN XY: 74340
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:9
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Osteogenesis imperfecta Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Oct 13, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not provided Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 30, 2020 | This variant is associated with the following publications: (PMID: 21884818) - |
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2022 | COL1A1: BS1, BS2 - |
Ehlers-Danlos syndrome, arthrochalasia type Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Infantile cortical hyperostosis Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Benign:1
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 11, 2015 | - - |
Ehlers-Danlos syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 14, 2022 | - - |
COL1A1-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 07, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2020 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Osteogenesis imperfecta type I Benign:1
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 25, 2023 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at