rs761895918
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_000088.4(COL1A1):c.4369G>C(p.Asp1457His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1457N) has been classified as Likely benign.
Frequency
Consequence
NM_000088.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.4369G>C | p.Asp1457His | missense_variant | 51/51 | ENST00000225964.10 | |
COL1A1 | XM_011524341.2 | c.4171G>C | p.Asp1391His | missense_variant | 48/48 | ||
COL1A1 | XM_005257058.5 | c.4099G>C | p.Asp1367His | missense_variant | 49/49 | ||
COL1A1 | XM_005257059.5 | c.3451G>C | p.Asp1151His | missense_variant | 38/38 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL1A1 | ENST00000225964.10 | c.4369G>C | p.Asp1457His | missense_variant | 51/51 | 1 | NM_000088.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250850Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135658
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461862Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727228
GnomAD4 genome ? Cov.: 29
ClinVar
Submissions by phenotype
Osteogenesis imperfecta type I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with osteogenesis imperfecta types I-IV, and other conditions (various MIM#s). Missense variants affecting the glycine residue of the Gly-X-Y triple helix motif have a dominant negative effect and result in severe disease, while loss of function causes milder phenotypes (PMID:12362985). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to histidine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2; highest allele frequency: 6 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated fibrillar collagen C-terminal domain (Pfam). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The variant p.(Asp1457Asn) has been reported twice in ClinVar as a variant of unknown significance. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at