chr17-68877520-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001288985.2(ABCA8):c.4198C>T(p.Arg1400Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,612,412 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )
Consequence
ABCA8
NM_001288985.2 missense, splice_region
NM_001288985.2 missense, splice_region
Scores
2
7
10
Splicing: ADA: 0.001498
2
Clinical Significance
Conservation
PhyloP100: -0.170
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCA8 | NM_001288985.2 | c.4198C>T | p.Arg1400Trp | missense_variant, splice_region_variant | 33/40 | ENST00000586539.6 | |
LOC105371874 | XR_001752986.3 | n.2589G>A | non_coding_transcript_exon_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCA8 | ENST00000586539.6 | c.4198C>T | p.Arg1400Trp | missense_variant, splice_region_variant | 33/40 | 1 | NM_001288985.2 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152048Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000441 AC: 11AN: 249632Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134796
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GnomAD4 exome AF: 0.0000342 AC: 50AN: 1460364Hom.: 0 Cov.: 30 AF XY: 0.0000317 AC XY: 23AN XY: 726422
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152048Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74274
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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 16, 2023 | The c.4078C>T (p.R1360W) alteration is located in exon 31 (coding exon 30) of the ABCA8 gene. This alteration results from a C to T substitution at nucleotide position 4078, causing the arginine (R) at amino acid position 1360 to be replaced by a tryptophan (W). 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
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.
MutationTaster
Benign
N;N;N
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;.;.
REVEL
Uncertain
Sift
Pathogenic
D;.;.
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at