17-50190093-G-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4BP6BS2
The NM_000088.4(COL1A1):āc.2467C>Gā(p.Pro823Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000382 in 1,613,440 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000088.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL1A1 | NM_000088.4 | c.2467C>G | p.Pro823Ala | missense_variant | Exon 36 of 51 | ENST00000225964.10 | NP_000079.2 | |
COL1A1 | XM_011524341.2 | c.2269C>G | p.Pro757Ala | missense_variant | Exon 33 of 48 | XP_011522643.1 | ||
COL1A1 | XM_005257058.5 | c.2467C>G | p.Pro823Ala | missense_variant | Exon 36 of 49 | XP_005257115.2 | ||
COL1A1 | XM_005257059.5 | c.1549C>G | p.Pro517Ala | missense_variant | Exon 23 of 38 | XP_005257116.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000290 AC: 44AN: 151782Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000343 AC: 86AN: 250466Hom.: 0 AF XY: 0.000391 AC XY: 53AN XY: 135662
GnomAD4 exome AF: 0.000392 AC: 573AN: 1461658Hom.: 0 Cov.: 37 AF XY: 0.000384 AC XY: 279AN XY: 727132
GnomAD4 genome AF: 0.000290 AC: 44AN: 151782Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15AN XY: 74138
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome Uncertain:1
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not provided Uncertain:1
Has been reported as a variant of uncertain significance in a female with bleeding diathesis (Fager Ferrari et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat. Although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (HGMD).; This variant is associated with the following publications: (PMID: 33161638) -
Infantile cortical hyperostosis Uncertain: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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Osteogenesis imperfecta 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
COL1A1-related disorder Benign:1
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). -
Ehlers-Danlos syndrome, arthrochalasia type 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. -
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. -
Osteogenesis imperfecta type I Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at