rs61731906

Positions:

• chr11-68775362-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001876.4(CPT1A):​c.1529C>T​(p.Pro510Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,614,196 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (8 hom.)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.63

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057145357).
• BP6: Variant 11-68775362-G-A is Benign according to our data. Variant chr11-68775362-G-A is described in ClinVar as [Benign]. Clinvar id is 377754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00672 (1024/152322) while in subpopulation AFR AF= 0.0231 (960/41568). AF 95% confidence interval is 0.0219. There are 13 homozygotes in gnomad4. There are 472 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT1A	NM_001876.4	c.1529C>T	p.Pro510Leu	missense_variant	13/19	ENST00000265641.10	NP_001867.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT1A	ENST00000265641.10	c.1529C>T	p.Pro510Leu	missense_variant	13/19	1	NM_001876.4	ENSP00000265641.4
CPT1A	ENST00000376618.6	c.1529C>T	p.Pro510Leu	missense_variant	13/19	1		ENSP00000365803.2
CPT1A	ENST00000540367.5	c.1529C>T	p.Pro510Leu	missense_variant	12/18	1		ENSP00000439084.1
CPT1A	ENST00000539743.5	c.1529C>T	p.Pro510Leu	missense_variant	12/18	5		ENSP00000446108.1

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1017 AN: 152204 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00169 AC: 424 AN: 251474 Hom.: 4 AF XY: 0.00122 AC XY: 166 AN XY: 135914

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000621 AC: 908 AN: 1461874 Hom.: 8 Cov.: 30 AF XY: 0.000517 AC XY: 376 AN XY: 727238

Gnomad4 AFR exome AF: 0.0213

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00672 AC: 1024 AN: 152322 Hom.: 13 Cov.: 32 AF XY: 0.00634 AC XY: 472 AN XY: 74494

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00118 Hom.: 3

Bravo AF: 0.00761

ESP6500AA AF: 0.0220 AC: 97

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00203 AC: 246

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carnitine palmitoyl transferase 1A deficiency Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 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
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Benign	0.70
DEOGEN2	Uncertain	0.65	.;.;D;D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	.;T;.;T
MetaRNN	Benign	0.0057	T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.7	L;L;L;L
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Uncertain	0.47
Sift	Benign	0.38	T;T;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.048	B;B;P;P
Vest4		0.23
MVP		0.85
MPC		0.43
ClinPred		0.044	T
GERP RS		4.2
Varity_R		0.063
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs61731906; hg19: chr11-68542830;