rs147563740

Positions:

• chr11-68760217-G-A
• chr11-68760217-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_001876.4(CPT1A):​c.2142+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000574 in 1,596,642 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (1 hom.)
• Consequence: CPT1A NM_001876.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002803
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.672

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 Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-68760217-G-A is Benign according to our data. Variant chr11-68760217-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 282930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-68760217-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000561 (811/1444414) while in subpopulation MID AF= 0.011 (49/4442). AF 95% confidence interval is 0.00857. There are 1 homozygotes in gnomad4_exome. There are 469 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT1A	NM_001876.4	c.2142+8C>T		splice_region_variant, intron_variant		ENST00000265641.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT1A	ENST00000265641.10	c.2142+8C>T		splice_region_variant, intron_variant		1	NM_001876.4	P1
CPT1A	ENST00000376618.6	c.2142+8C>T		splice_region_variant, intron_variant		1
CPT1A	ENST00000540367.5	c.2142+8C>T		splice_region_variant, intron_variant		1
CPT1A	ENST00000539743.5	c.2142+8C>T		splice_region_variant, intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.000684 AC: 104 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000799 AC: 187 AN: 233998 Hom.: 0 AF XY: 0.00101 AC XY: 128 AN XY: 126274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00233

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000909

Gnomad OTH exome AF: 0.00274

GnomAD4 exome AF: 0.000561 AC: 811 AN: 1444414 Hom.: 1 Cov.: 30 AF XY: 0.000653 AC XY: 469 AN XY: 717734

Gnomad4 AFR exome AF: 0.000663

Gnomad4 AMR exome AF: 0.000300

Gnomad4 ASJ exome AF: 0.000155

Gnomad4 EAS exome AF: 0.0000761

Gnomad4 SAS exome AF: 0.00205

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000429

Gnomad4 OTH exome AF: 0.00124

GnomAD4 genome AF: 0.000690 AC: 105 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000699 AC XY: 52 AN XY: 74424

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000716 Hom.: 0

Bravo AF: 0.000559

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -

Carnitine palmitoyl transferase 1A deficiency Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.34
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs147563740; hg19: chr11-68527685;