rs2228502

Positions:

• chr11-68781872-A-C
• chr11-68781872-A-G
• chr11-68781872-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001876.4(CPT1A):​c.1251T>G​(p.Phe417Leu) 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. Synonymous variant affecting the same amino acid position (i.e. F417F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.301

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 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001876.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT1A	NM_001876.4	c.1251T>G	p.Phe417Leu	missense_variant	11/19	ENST00000265641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT1A	ENST00000265641.10	c.1251T>G	p.Phe417Leu	missense_variant	11/19	1	NM_001876.4	P1
CPT1A	ENST00000376618.6	c.1251T>G	p.Phe417Leu	missense_variant	11/19	1
CPT1A	ENST00000540367.5	c.1251T>G	p.Phe417Leu	missense_variant	10/18	1
CPT1A	ENST00000539743.5	c.1251T>G	p.Phe417Leu	missense_variant	10/18	5		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 51

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	.;.;D;D
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	.;D;.;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.9	L;L;L;L
MutationTaster	Benign	0.00029	P;P;P;P
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Uncertain	0.59
Sift	Benign	0.032	D;D;D;D
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.91	P;P;B;B
Vest4		0.69
MutPred		0.58		Gain of ubiquitination at K413 (P = 0.123);Gain of ubiquitination at K413 (P = 0.123);Gain of ubiquitination at K413 (P = 0.123);Gain of ubiquitination at K413 (P = 0.123);
MVP		0.75
MPC		0.84
ClinPred		0.92	D
GERP RS		0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.76

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: rs2228502; hg19: chr11-68549340;