rs370388701
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BS1_Supporting
The NM_004370.6(COL12A1):c.2588G>A(p.Gly863Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000799 in 1,614,170 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000042 ( 0 hom. )
Consequence
COL12A1
NM_004370.6 missense
NM_004370.6 missense
Scores
6
10
3
Clinical Significance
Conservation
PhyloP100: 7.57
Genes affected
COL12A1 (HGNC:2188): (collagen type XII alpha 1 chain) This gene encodes the alpha chain of type XII collagen, a member of the FACIT (fibril-associated collagens with interrupted triple helices) collagen family. Type XII collagen is a homotrimer found in association with type I collagen, an association that is thought to modify the interactions between collagen I fibrils and the surrounding matrix. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, COL12A1
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000447 (68/152278) while in subpopulation AFR AF= 0.00159 (66/41572). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL12A1 | NM_004370.6 | c.2588G>A | p.Gly863Glu | missense_variant | 13/66 | ENST00000322507.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL12A1 | ENST00000322507.13 | c.2588G>A | p.Gly863Glu | missense_variant | 13/66 | 1 | NM_004370.6 | P4 | |
COL12A1 | ENST00000345356.10 | c.74-22678G>A | intron_variant | 1 | |||||
COL12A1 | ENST00000483888.6 | c.2588G>A | p.Gly863Glu | missense_variant | 13/65 | 5 | A1 | ||
COL12A1 | ENST00000416123.6 | c.2588G>A | p.Gly863Glu | missense_variant | 12/63 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000440 AC: 67AN: 152160Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000100 AC: 25AN: 249512Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135368
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GnomAD4 exome AF: 0.0000417 AC: 61AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27AN XY: 727246
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GnomAD4 genome ? AF: 0.000447 AC: 68AN: 152278Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35AN XY: 74466
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 25, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 18, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 27, 2022 | The c.2588G>A (p.G863E) alteration is located in exon 13 (coding exon 12) of the COL12A1 gene. This alteration results from a G to A substitution at nucleotide position 2588, causing the glycine (G) at amino acid position 863 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
COL12A1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 25, 2023 | The COL12A1 c.2588G>A variant is predicted to result in the amino acid substitution p.Gly863Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.19% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-75884876-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
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