rs80356800

Variant names:

• chr11-68793333-TC-T
• rs80356800
• NM_001876.4:c.948delG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001876.4(CPT1A):​c.948delG​(p.Ile317SerfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,134 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CPT1A NM_001876.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.155
• Publications: 2 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, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-68793333-TC-T is Pathogenic according to our data. Variant chr11-68793333-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9070.Status of the report is no_assertion_criteria_provided, 0 stars.

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.948delG	p.Ile317SerfsTer12	frameshift	Exon 9 of 19	NP_001867.2
	CPT1A	NM_001440358.1		c.948delG	p.Ile317SerfsTer12	frameshift	Exon 9 of 19	NP_001427287.1
	CPT1A	NM_001440359.1		c.948delG	p.Ile317SerfsTer12	frameshift	Exon 10 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.948delG	p.Ile317SerfsTer12	frameshift	Exon 9 of 19	ENSP00000265641.4
	CPT1A	ENST00000376618.6	TSL:1	c.948delG	p.Ile317SerfsTer12	frameshift	Exon 9 of 19	ENSP00000365803.2
	CPT1A	ENST00000540367.5	TSL:1	c.948delG	p.Ile317SerfsTer12	frameshift	Exon 8 of 18	ENSP00000439084.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459134 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725666

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26018

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5116

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111002

Other (OTH) AF: 0.00 AC: 0 AN: 60258

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Carnitine palmitoyl transferase 1A deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.15
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs80356800; hg19: chr11-68560801;