chr11-68760306-G-C

Variant names:

• chr11-68760306-G-C
• rs1269472669
• NM_001876.4:c.2061C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001876.4(CPT1A):​c.2061C>G​(p.Ser687Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S687S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.79
• 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, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 11-68760306-G-C is Pathogenic according to our data. Variant chr11-68760306-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 463966.Status of the report is criteria_provided_single_submitter, 1 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.2061C>G	p.Ser687Arg	missense	Exon 17 of 19	NP_001867.2	P50416-1
	CPT1A	NM_001440358.1		c.2061C>G	p.Ser687Arg	missense	Exon 17 of 19	NP_001427287.1
	CPT1A	NM_001440359.1		c.2061C>G	p.Ser687Arg	missense	Exon 18 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.2061C>G	p.Ser687Arg	missense	Exon 17 of 19	ENSP00000265641.4	P50416-1
	CPT1A	ENST00000376618.6	TSL:1	c.2061C>G	p.Ser687Arg	missense	Exon 17 of 19	ENSP00000365803.2	P50416-2
	CPT1A	ENST00000540367.5	TSL:1	c.2061C>G	p.Ser687Arg	missense	Exon 16 of 18	ENSP00000439084.1	P50416-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460394 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726374

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

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 85902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5526

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111528

Other (OTH) AF: 0.00 AC: 0 AN: 60338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		1.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.81		Gain of catalytic residue at S687 (P = 0.023)
MVP		0.92
MPC		1.3
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.93
gMVP		0.93
Mutation Taster		=42/58	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: rs1269472669; hg19: chr11-68527774;