rs199757996
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_004370.6(COL12A1):c.3899C>T(p.Ala1300Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,613,686 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000060 ( 0 hom. )
Consequence
COL12A1
NM_004370.6 missense
NM_004370.6 missense
Scores
2
3
10
Clinical Significance
Conservation
PhyloP100: 7.75
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 Likely_benign. Variant got -1 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, COL12A1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.17996553).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL12A1 | NM_004370.6 | c.3899C>T | p.Ala1300Val | missense_variant | 20/66 | ENST00000322507.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL12A1 | ENST00000322507.13 | c.3899C>T | p.Ala1300Val | missense_variant | 20/66 | 1 | NM_004370.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152066Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 249224Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135192
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GnomAD4 exome AF: 0.0000602 AC: 88AN: 1461620Hom.: 0 Cov.: 31 AF XY: 0.0000591 AC XY: 43AN XY: 727120
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74284
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2021 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 568941; Landrum et al., 2016) - |
Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1300 of the COL12A1 protein (p.Ala1300Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with COL12A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 568941). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL12A1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Sift4G
Benign
T;T;T;T;T
Polyphen
0.52, 0.012
.;P;B;.;.
Vest4
MVP
MPC
0.54
ClinPred
D
GERP RS
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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