chr11-68757706-G-T

Position:

• chr11-68757706-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001876.4(CPT1A):​c.2260C>A​(p.Leu754Met) 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. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L754L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT1A	NM_001876.4	c.2260C>A	p.Leu754Met	missense_variant	19/19	ENST00000265641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT1A	ENST00000265641.10	c.2260C>A	p.Leu754Met	missense_variant	19/19	1	NM_001876.4	P1
CPT1A	ENST00000376618.6	c.2235+1863C>A		intron_variant		1
CPT1A	ENST00000540367.5	c.2235+1863C>A		intron_variant		1
CPT1A	ENST00000539743.5	c.2260C>A	p.Leu754Met	missense_variant	18/18	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Carnitine palmitoyl transferase 1A deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt CPT1A protein function. This variant has not been reported in the literature in individuals affected with CPT1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 754 of the CPT1A protein (p.Leu754Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D;D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.51	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.70	D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.97	N;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.79	P;P
Vest4		0.40
MutPred		0.80		Gain of disorder (P = 0.0485);Gain of disorder (P = 0.0485);
MVP		0.67
MPC		0.90
ClinPred		0.69	D
GERP RS		-0.56
Varity_R		0.22
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr11-68525174; COSMIC: COSV55753552; COSMIC: COSV55753552;