rs140958507

Variant names:

• chr11-68794820-C-T
• rs140958507
• NM_001876.4:c.863G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001876.4(CPT1A):​c.863G>A​(p.Arg288Gln) variant causes a missense change. The variant allele was found at a frequency of 0.007 in 1,613,936 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R288W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (53 hom.)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.58
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0125771165).
• BP6: Variant 11-68794820-C-T is Benign according to our data. Variant chr11-68794820-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 203655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00473 (720/152288) while in subpopulation NFE AF = 0.00826 (562/68036). AF 95% confidence interval is 0.00769. There are 2 homozygotes in GnomAd4. There are 323 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.863G>A	p.Arg288Gln	missense	Exon 8 of 19	NP_001867.2	P50416-1
	CPT1A	NM_001440358.1		c.863G>A	p.Arg288Gln	missense	Exon 8 of 19	NP_001427287.1
	CPT1A	NM_001440359.1		c.863G>A	p.Arg288Gln	missense	Exon 9 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.863G>A	p.Arg288Gln	missense	Exon 8 of 19	ENSP00000265641.4	P50416-1
	CPT1A	ENST00000376618.6	TSL:1	c.863G>A	p.Arg288Gln	missense	Exon 8 of 19	ENSP00000365803.2	P50416-2
	CPT1A	ENST00000540367.5	TSL:1	c.863G>A	p.Arg288Gln	missense	Exon 7 of 18	ENSP00000439084.1	P50416-2

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 720 AN: 152170 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00538

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00826

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00530 AC: 1334 AN: 251488 AF XY: 0.00525

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00610

Gnomad NFE exome AF: 0.00956

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00723 AC: 10570 AN: 1461648 Hom.: 53 Cov.: 31 AF XY: 0.00689 AC XY: 5010 AN XY: 727150

African (AFR) AF: 0.00128 AC: 43 AN: 33474

American (AMR) AF: 0.00116 AC: 52 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39696

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86252

European-Finnish (FIN) AF: 0.00730 AC: 390 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00863 AC: 9592 AN: 1111798

Other (OTH) AF: 0.00671 AC: 405 AN: 60388

GnomAD4 genome AF: 0.00473 AC: 720 AN: 152288 Hom.: 2 Cov.: 33 AF XY: 0.00434 AC XY: 323 AN XY: 74454

African (AFR) AF: 0.00144 AC: 60 AN: 41556

American (AMR) AF: 0.00170 AC: 26 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00538 AC: 57 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00826 AC: 562 AN: 68036

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00683 Hom.: 12

Bravo AF: 0.00427

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00815 AC: 70

ExAC AF: 0.00586 AC: 711

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00725

EpiControl AF: 0.00670

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Carnitine palmitoyl transferase 1A deficiency (4)
-	-	2	not provided (2)
-	-	1	CPT1A-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.049	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.6
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.027	D
Polyphen		0.81	P
Vest4		0.35
MVP		0.87
MPC		0.73
ClinPred		0.047	T
GERP RS		3.2
Varity_R		0.56
gMVP		0.81
Mutation Taster		=92/8	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: rs140958507; hg19: chr11-68562288; COSMIC: COSV99039713;