rs2229738

chr11-68794860-C-Gchr11-68794860-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001876.4(CPT1A):c.823G>C(p.Ala275Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A275T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.806

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT1A	NM_001876.4	c.823G>C	p.Ala275Pro	missense_variant	8/19	ENST00000265641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT1A	ENST00000265641.10	c.823G>C	p.Ala275Pro	missense_variant	8/19	1	NM_001876.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	16
Dann	Uncertain	0.98
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.45	N
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.4	N;N;N;N;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.023	D;D;D;D;D
Sift4G	Uncertain	0.029	D;D;D;D;D
Polyphen		0.83	P;P;P;P;.
Vest4		0.60
MutPred		0.79		Loss of MoRF binding (P = 0.0703);Loss of MoRF binding (P = 0.0703);Loss of MoRF binding (P = 0.0703);Loss of MoRF binding (P = 0.0703);.;
MVP		0.93
MPC		1.2
ClinPred		0.86	D
GERP RS		0.17
Varity_R		0.77
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229738; hg19: chr11-68562328;