11-68757673-A-G

Position:

• chr11-68757673-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001876.4(CPT1A):​c.2293T>C​(p.Phe765Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT1A	NM_001876.4	c.2293T>C	p.Phe765Leu	missense_variant	19/19	ENST00000265641.10	NP_001867.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT1A	ENST00000265641.10	c.2293T>C	p.Phe765Leu	missense_variant	19/19	1	NM_001876.4	ENSP00000265641.4
CPT1A	ENST00000376618.6	c.2235+1896T>C		intron_variant		1		ENSP00000365803.2
CPT1A	ENST00000540367.5	c.2235+1896T>C		intron_variant		1		ENSP00000439084.1
CPT1A	ENST00000539743.5	c.2293T>C	p.Phe765Leu	missense_variant	18/18	5		ENSP00000446108.1

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

Labcorp Genetics (formerly Invitae), Labcorp

Mar 28, 2019

This variant has not been reported in the literature in individuals with CPT1A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 765 of the CPT1A protein (p.Phe765Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.83	D;D
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.68	.;T
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.66	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Uncertain	0.51
Sift	Benign	0.047	D;D
Sift4G	Uncertain	0.059	T;T
Polyphen		0.99	D;D
Vest4		0.45
MutPred		0.57		Gain of catalytic residue at F765 (P = 0.0097);Gain of catalytic residue at F765 (P = 0.0097);
MVP		0.62
MPC		0.54
ClinPred		0.96	D
GERP RS		3.8
Varity_R		0.42
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1946717191; hg19: chr11-68525141;