chr7-94429329-A-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBP6
The NM_000089.4(COL1A2):āc.3853A>Cā(p.Asn1285His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000891 in 1,614,148 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000089.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL1A2 | NM_000089.4 | c.3853A>C | p.Asn1285His | missense_variant | Exon 51 of 52 | ENST00000297268.11 | NP_000080.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL1A2 | ENST00000297268.11 | c.3853A>C | p.Asn1285His | missense_variant | Exon 51 of 52 | 1 | NM_000089.4 | ENSP00000297268.6 | ||
COL1A2 | ENST00000464916.1 | n.901A>C | non_coding_transcript_exon_variant | Exon 3 of 4 | 2 | |||||
COL1A2 | ENST00000481570.5 | n.4634A>C | non_coding_transcript_exon_variant | Exon 8 of 8 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000552 AC: 84AN: 152186Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000470 AC: 118AN: 251074Hom.: 0 AF XY: 0.000442 AC XY: 60AN XY: 135690
GnomAD4 exome AF: 0.000926 AC: 1354AN: 1461844Hom.: 1 Cov.: 33 AF XY: 0.000847 AC XY: 616AN XY: 727216
GnomAD4 genome AF: 0.000552 AC: 84AN: 152304Hom.: 0 Cov.: 31 AF XY: 0.000550 AC XY: 41AN XY: 74486
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
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not specified Uncertain:1Benign:1
The N1285H variant in the COL1A2 gene has published as a variant of uncertain significance in a patient with OI who also harbored a known pathogenic variant in a different gene (Pollitt et al., 2006). Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports N1285H was observed in 10/8600 alleles (0.12%) from individuals of European background, indicating it may be a rare variant in this population. The N1285H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. However, in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret N1285H as a variant of uncertain significance.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time. -
Variant summary: COL1A2 c.3853A>C (p.Asn1285His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251220 control chromosomes. The observed variant frequency is approximately 17 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A2 causing Osteogenesis Imperfecta phenotype (2.8e-05). c.3853A>C has been reported in the literature in one individual affected with Osteogenesis Imperfecta (Pollitt_2006). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 16786509). ClinVar contains an entry for this variant (Variation ID: 373178). Based on the evidence outlined above, the variant was classified as likely benign. -
Osteogenesis imperfecta Uncertain:1Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
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Osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4303789:Ehlers-Danlos syndrome, cardiac valvular type;C5436847:Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2;CN293783:Ehlers-danlos syndrome, arthrochalasia type, 2 Uncertain:1
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Ehlers-Danlos syndrome Uncertain:1
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Postmenopausal osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4303789:Ehlers-Danlos syndrome, cardiac valvular type;CN293783:Ehlers-danlos syndrome, arthrochalasia type, 2 Uncertain:1
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Ehlers-danlos syndrome, arthrochalasia type, 2 Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Osteogenesis imperfecta type I;C0268335:Ehlers-Danlos syndrome, classic type, 1 Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as likely 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at