rs375673671
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting
The NM_004370.6(COL12A1):c.607C>A(p.Leu203Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000391 in 1,613,192 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
Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
COL12A1
NM_004370.6 missense
NM_004370.6 missense
Scores
1
8
10
Clinical Significance
Conservation
PhyloP100: 4.11
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 -2 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, COL12A1
BP4
?
Computational evidence support a benign effect (MetaRNN=0.107500225).
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00021 (32/152042) while in subpopulation AFR AF= 0.000699 (29/41502). AF 95% confidence interval is 0.000499. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. 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.607C>A | p.Leu203Ile | missense_variant | 6/66 | ENST00000322507.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL12A1 | ENST00000322507.13 | c.607C>A | p.Leu203Ile | missense_variant | 6/66 | 1 | NM_004370.6 | P4 | |
COL12A1 | ENST00000345356.10 | c.73+13117C>A | intron_variant | 1 | |||||
COL12A1 | ENST00000483888.6 | c.607C>A | p.Leu203Ile | missense_variant | 6/65 | 5 | A1 | ||
COL12A1 | ENST00000416123.6 | c.607C>A | p.Leu203Ile | missense_variant | 5/63 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000211 AC: 32AN: 151924Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000646 AC: 16AN: 247854Hom.: 0 AF XY: 0.0000594 AC XY: 8AN XY: 134572
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461150Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 726862
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GnomAD4 genome ? AF: 0.000210 AC: 32AN: 152042Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74332
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 10, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 24, 2023 | 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 - |
Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 09, 2021 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 11, 2024 | The c.607C>A (p.L203I) alteration is located in exon 6 (coding exon 5) of the COL12A1 gene. This alteration results from a C to A substitution at nucleotide position 607, causing the leucine (L) at amino acid position 203 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
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