rs80356787

chr11-68784899-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001876.4(CPT1A):c.1079A>G(p.Glu360Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E360E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.74

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-68784899-T-C is Pathogenic according to our data. Variant chr11-68784899-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9062.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT1A	NM_001876.4	c.1079A>G	p.Glu360Gly	missense_variant	10/19	ENST00000265641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT1A	ENST00000265641.10	c.1079A>G	p.Glu360Gly	missense_variant	10/19	1	NM_001876.4	P1
CPT1A	ENST00000376618.6	c.1079A>G	p.Glu360Gly	missense_variant	10/19	1
CPT1A	ENST00000540367.5	c.1079A>G	p.Glu360Gly	missense_variant	9/18	1
CPT1A	ENST00000539743.5	c.1079A>G	p.Glu360Gly	missense_variant	9/18	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Carnitine palmitoyl transferase 1A deficiency Pathogenic:1 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2002	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.7	H;H;H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.91
MutPred		0.87		Gain of MoRF binding (P = 0.0274);Gain of MoRF binding (P = 0.0274);Gain of MoRF binding (P = 0.0274);Gain of MoRF binding (P = 0.0274);
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.81

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: rs80356787; hg19: chr11-68552367;