11-68757728-A-C

Variant summary

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

The NM_001876.4(CPT1A):c.2238T>G(p.Asp746Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D746Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CPT1A NM_001876.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.664

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	UniProt
CPT1A	NM_001876.4	c.2238T>G	p.Asp746Glu	missense_variant, splice_region_variant	19/19	ENST00000265641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT1A	ENST00000265641.10	c.2238T>G	p.Asp746Glu	missense_variant, splice_region_variant	19/19	1	NM_001876.4	P1
CPT1A	ENST00000376618.6	c.2235+1841T>G		intron_variant		1
CPT1A	ENST00000540367.5	c.2235+1841T>G		intron_variant		1
CPT1A	ENST00000539743.5	c.2238T>G	p.Asp746Glu	missense_variant, splice_region_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

Dec 07, 2021

This variant has not been reported in the literature in individuals affected with CPT1A-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1051841). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 746 of the CPT1A protein (p.Asp746Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;D
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.98	D;D
Vest4		0.40
MutPred		0.75		Loss of loop (P = 0.0986);Loss of loop (P = 0.0986);
MVP		0.89
MPC		1.1
ClinPred		0.99	D
GERP RS		-0.39
Varity_R		0.80
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: chr11-68525196;