rs189174414
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_001876.4(CPT1A):āc.1364A>Cā(p.Lys455Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.00020 ( 0 hom., cov: 33)
Exomes š: 0.000079 ( 0 hom. )
Consequence
CPT1A
NM_001876.4 missense
NM_001876.4 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 7.78
Genes affected
CPT1A (HGNC:2328): (carnitine palmitoyltransferase 1A) The mitochondrial oxidation of long-chain fatty acids is initiated by the sequential action of carnitine palmitoyltransferase I (which is located in the outer membrane and is detergent-labile) and carnitine palmitoyltransferase II (which is located in the inner membrane and is detergent-stable), together with a carnitine-acylcarnitine translocase. CPT I is the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane and its deficiency results in a decreased rate of fatty acid beta-oxidation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-68780734-T-G is Pathogenic according to our data. Variant chr11-68780734-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CPT1A | NM_001876.4 | c.1364A>C | p.Lys455Thr | missense_variant | 12/19 | ENST00000265641.10 | NP_001867.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CPT1A | ENST00000265641.10 | c.1364A>C | p.Lys455Thr | missense_variant | 12/19 | 1 | NM_001876.4 | ENSP00000265641.4 | ||
CPT1A | ENST00000376618.6 | c.1364A>C | p.Lys455Thr | missense_variant | 12/19 | 1 | ENSP00000365803.2 | |||
CPT1A | ENST00000540367.5 | c.1364A>C | p.Lys455Thr | missense_variant | 11/18 | 1 | ENSP00000439084.1 | |||
CPT1A | ENST00000539743.5 | c.1364A>C | p.Lys455Thr | missense_variant | 11/18 | 5 | ENSP00000446108.1 |
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152250Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000223 AC: 56AN: 251492Hom.: 0 AF XY: 0.000221 AC XY: 30AN XY: 135920
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GnomAD4 exome AF: 0.0000787 AC: 115AN: 1461756Hom.: 0 Cov.: 31 AF XY: 0.0000660 AC XY: 48AN XY: 727178
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GnomAD4 genome AF: 0.000203 AC: 31AN: 152368Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74514
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Carnitine palmitoyl transferase 1A deficiency Pathogenic:5
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 23, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 08, 2023 | For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt CPT1A protein function. ClinVar contains an entry for this variant (Variation ID: 189151). This missense change has been observed in individual(s) with CPT1A-related conditions (PMID: 21962599). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs189174414, gnomAD 0.2%). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 455 of the CPT1A protein (p.Lys455Thr). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 03, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 09, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 02, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15970898, 17060594, 21962599, 17060592) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
.;.;D;D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Benign
T;T;T;T
Polyphen
D;D;D;D
Vest4
MVP
MPC
1.4
ClinPred
D
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