chr11-68774781-CAA-C

Variant names:

• chr11-68774781-CAA-C
• rs1169875761
• NM_001876.4:c.1575+533_1575+534delTT

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001876.4(CPT1A):​c.1575+533_1575+534delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000332 in 54,264 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: 𝑓 0.00033 (0 hom., cov: 28)
• Consequence: CPT1A NM_001876.4 intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.733
• 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, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-68774781-CAA-C is Pathogenic according to our data. Variant chr11-68774781-CAA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 9064.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPT1A	NM_001876.4	c.1575+533_1575+534delTT		intron_variant	Intron 13 of 18	ENST00000265641.10	NP_001867.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPT1A	ENST00000265641.10	c.1575+533_1575+534delTT		intron_variant	Intron 13 of 18	1	NM_001876.4	ENSP00000265641.4
CPT1A	ENST00000376618.6	c.1575+533_1575+534delTT		intron_variant	Intron 13 of 18	1		ENSP00000365803.2
CPT1A	ENST00000540367.5	c.1575+533_1575+534delTT		intron_variant	Intron 12 of 17	1		ENSP00000439084.1
CPT1A	ENST00000539743.5	c.1575+533_1575+534delTT		intron_variant	Intron 12 of 17	5		ENSP00000446108.1

Frequencies

GnomAD3 genomes AF: 0.000332 AC: 18 AN: 54240 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000449

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00357

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000190

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000332 AC: 18 AN: 54264 Hom.: 0 Cov.: 28 AF XY: 0.000353 AC XY: 9 AN XY: 25504

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

African (AFR) AF: 0.000204 AC: 3 AN: 14704

American (AMR) AF: 0.000448 AC: 2 AN: 4464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1586

East Asian (EAS) AF: 0.00 AC: 0 AN: 2014

South Asian (SAS) AF: 0.00 AC: 0 AN: 1744

European-Finnish (FIN) AF: 0.00357 AC: 8 AN: 2238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 106

European-Non Finnish (NFE) AF: 0.000190 AC: 5 AN: 26350

Other (OTH) AF: 0.00 AC: 0 AN: 692

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000000275635), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 10

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Carnitine palmitoyl transferase 1A deficiency Pathogenic:1

Aug 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.73
Mutation Taster		=6/94	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: rs1169875761; hg19: chr11-68542249;