17-68869768-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001288985.2(ABCA8):āc.4643T>Cā(p.Leu1548Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,612,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000059 ( 0 hom., cov: 32)
Exomes š: 0.000018 ( 0 hom. )
Consequence
ABCA8
NM_001288985.2 missense
NM_001288985.2 missense
Scores
5
11
3
Clinical Significance
Conservation
PhyloP100: 8.57
Genes affected
ABCA8 (HGNC:38): (ATP binding cassette subfamily A member 8) 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, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. The encoded protein may regulate lipid metabolism and be involved in the formation and maintenance of myelin. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.843
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ABCA8 | NM_001288985.2 | c.4643T>C | p.Leu1548Pro | missense_variant | 38/40 | ENST00000586539.6 | NP_001275914.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ABCA8 | ENST00000586539.6 | c.4643T>C | p.Leu1548Pro | missense_variant | 38/40 | 1 | NM_001288985.2 | ENSP00000467271.1 | ||
ABCA8 | ENST00000430352.6 | c.4628T>C | p.Leu1543Pro | missense_variant | 37/39 | 1 | ENSP00000402814.3 | |||
ABCA8 | ENST00000269080.6 | c.4523T>C | p.Leu1508Pro | missense_variant | 36/38 | 1 | ENSP00000269080.1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152210Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251010Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135674
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GnomAD4 exome AF: 0.0000185 AC: 27AN: 1459894Hom.: 0 Cov.: 29 AF XY: 0.0000124 AC XY: 9AN XY: 726396
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74366
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 03, 2022 | The c.4523T>C (p.L1508P) alteration is located in exon 36 (coding exon 35) of the ABCA8 gene. This alteration results from a T to C substitution at nucleotide position 4523, causing the leucine (L) at amino acid position 1508 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
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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