11-68757723-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001876.4(CPT1A):c.2243A>T(p.His748Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,124 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CPT1A
NM_001876.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 6.10

Variant links:

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]

CPT1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPT1A	NM_001876.4 link	c.2243A>T	p.His748Leu	missense_variant	Exon 19 of 19	ENST00000265641.10	NP_001867.2	P50416-1A0A024R5F4Q8WZ48B2RAQ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CPT1A	ENST00000265641.10 link	c.2243A>T	p.His748Leu	missense_variant	Exon 19 of 19	1	NM_001876.4	ENSP00000265641.4	P50416-1
CPT1A	ENST00000376618.6 link	c.2235+1846A>T		intron_variant	Intron 18 of 18	1		ENSP00000365803.2	P50416-2
CPT1A	ENST00000540367.5 link	c.2235+1846A>T		intron_variant	Intron 17 of 17	1		ENSP00000439084.1	P50416-2
CPT1A	ENST00000539743.5 link	c.2243A>T	p.His748Leu	missense_variant	Exon 18 of 18	5		ENSP00000446108.1	P50416-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249060

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134840

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460936

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726840

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000284

Hom.:

Bravo

AF:

0.0000416

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Carnitine palmitoyl transferase 1A deficiency

Uncertain:2

Sep 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine with leucine at codon 748 of the CPT1A protein (p.His748Leu). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CPT1A-related conditions. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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

Benign

0.18

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Benign

0.95

DEOGEN2

Pathogenic

0.86

D;D

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

.;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.1

D;D

REVEL

Pathogenic

0.76

Sift

Benign

0.17

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.99

D;D

Vest4

0.56

MVP

0.93

MPC

0.53

ClinPred

0.60

GERP RS

5.0

Varity_R

0.69

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over