11-68775398-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001876.4(CPT1A):​c.1493A>C​(p.Tyr498Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

CPT1A
NM_001876.4 missense

Scores

10
8
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.85
Variant links:
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CPT1ANM_001876.4 linkc.1493A>C p.Tyr498Ser missense_variant Exon 13 of 19 ENST00000265641.10 NP_001867.2 P50416-1A0A024R5F4Q8WZ48B2RAQ8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CPT1AENST00000265641.10 linkc.1493A>C p.Tyr498Ser missense_variant Exon 13 of 19 1 NM_001876.4 ENSP00000265641.4 P50416-1
CPT1AENST00000376618.6 linkc.1493A>C p.Tyr498Ser missense_variant Exon 13 of 19 1 ENSP00000365803.2 P50416-2
CPT1AENST00000540367.5 linkc.1493A>C p.Tyr498Ser missense_variant Exon 12 of 18 1 ENSP00000439084.1 P50416-2
CPT1AENST00000539743.5 linkc.1493A>C p.Tyr498Ser missense_variant Exon 12 of 18 5 ENSP00000446108.1 P50416-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461884
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.88
.;.;D;D
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
.;D;.;D
M_CAP
Uncertain
0.099
D
MetaRNN
Pathogenic
0.98
D;D;D;D
MetaSVM
Uncertain
0.77
D
MutationAssessor
Uncertain
2.9
M;M;M;M
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-7.9
D;D;D;D
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.92
MVP
0.96
MPC
1.5
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.93
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-68542866; API