rs28936374

Positions:

• chr11-68760241-C-T

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.2126G>A​(p.Gly709Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G709R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.71

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, 0.982
• PP5: Variant 11-68760241-C-T is Pathogenic according to our data. Variant chr11-68760241-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9069.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.2126G>A	p.Gly709Glu	missense_variant	17/19	ENST00000265641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT1A	ENST00000265641.10	c.2126G>A	p.Gly709Glu	missense_variant	17/19	1	NM_001876.4	P1
CPT1A	ENST00000376618.6	c.2126G>A	p.Gly709Glu	missense_variant	17/19	1
CPT1A	ENST00000540367.5	c.2126G>A	p.Gly709Glu	missense_variant	16/18	1
CPT1A	ENST00000539743.5	c.2126G>A	p.Gly709Glu	missense_variant	16/18	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458078 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725034

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: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 12, 2003	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.4	M;M;M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.6	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.96
MutPred		0.85		Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);Gain of solvent accessibility (P = 0.012);
MVP		0.93
MPC		1.4
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.95

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: rs28936374; hg19: chr11-68527709;