rs1553520468
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_173076.3(ABCA12):c.6234-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
ABCA12
NM_173076.3 splice_acceptor
NM_173076.3 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.84
Genes affected
ABCA12 (HGNC:14637): (ATP binding cassette subfamily A member 12) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This encoded protein is a member of the ABC1 subfamily, which is the only major ABC subfamily found exclusively in multicellular eukaryotes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 2-214955362-C-G is Pathogenic according to our data. Variant chr2-214955362-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 488389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214955362-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA12 | NM_173076.3 | c.6234-1G>C | splice_acceptor_variant | ENST00000272895.12 | |||
SNHG31 | NR_110292.1 | n.445-6448C>G | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA12 | ENST00000272895.12 | c.6234-1G>C | splice_acceptor_variant | 1 | NM_173076.3 | P1 | |||
SNHG31 | ENST00000670391.1 | n.438-6448C>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive congenital ichthyosis 4B Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing;provider interpretation | Kids Neuroscience Centre, Sydney Children's Hospitals Network | - | The c.6234-1G>C variant induces exon 43 skipping (p.Tyr2079Leufs*2) causing a frameshift, encoding a missense amino acid and a premature termination codon. These transcripts are targeted for nonsense-mediated decay. Mis-spliced ABCA12 transcripts with exon 43 skipping that escape nonsense-mediated decay encode ABCA12 proteins missing 516 amino acids from the C-terminus p.(Tyr2079_Ser2595del), including the entire C-terminal ABC transporter domain. - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 24, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital ichthyosis 4A (MIM#601277) and congenital harlequin ichthyosis 4B (MIM#242500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA studies using patient EBV-transformed lymphoblasts demonstrated out-of-frame skipping of exon 43 which resulted in a frameshift and subsequent nonsense-mediated decay of the resulting protein (Splicing Diagnostics, Kids Neuroscience Centre). (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are multiple likely pathogenic or pathogenic NMD-predicted variants that have been previously reported (DECIPHER). (SP) 0807 - This variant has no previous evidence of pathogenicity. However, it should be noted that the proband of this family has been reported by VCGS and our collaborators (ClinVar, PMID: 29543227). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at