NM_001876.4:c.2243A>G

Variant names:

• chr11-68757723-T-C
• rs900349852
• NM_001876.4:c.2243A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001876.4(CPT1A):​c.2243A>G​(p.His748Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,936 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H748L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.10
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• carnitine palmitoyl transferase 1A deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001876.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1A	NM_001876.4	MANE Select	c.2243A>G	p.His748Arg	missense	Exon 19 of 19	NP_001867.2	P50416-1
	CPT1A	NM_001440358.1		c.2243A>G	p.His748Arg	missense	Exon 19 of 19	NP_001427287.1
	CPT1A	NM_001440359.1		c.2243A>G	p.His748Arg	missense	Exon 20 of 20	NP_001427288.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1A	ENST00000265641.10	TSL:1 MANE Select	c.2243A>G	p.His748Arg	missense	Exon 19 of 19	ENSP00000265641.4	P50416-1
	CPT1A	ENST00000376618.6	TSL:1	c.2235+1846A>G		intron	N/A	ENSP00000365803.2	P50416-2
	CPT1A	ENST00000540367.5	TSL:1	c.2235+1846A>G		intron	N/A	ENSP00000439084.1	P50416-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460936 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726840

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111456

Other (OTH) AF: 0.00 AC: 0 AN: 60346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.82	D
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.0030
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	-0.032	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.69
Sift	Benign	0.24	T
Sift4G	Benign	0.32	T
Polyphen		0.13	B
Vest4		0.43
MutPred		0.46		Gain of phosphorylation at S747 (P = 0.0877)
MVP		0.94
MPC		0.53
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.59
gMVP		0.54
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs900349852; hg19: chr11-68525191;