chr11-68760217-G-A

Variant names:

• chr11-68760217-G-A
• rs147563740
• NM_001876.4:c.2142+8C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. 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:8
• Conservation: PhyloP100: 0.672
• 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: Benign. The variant received -16 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 282930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 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 GnomAdExome4. There are 469 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

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.2142+8C>T		splice_region intron	N/A	NP_001867.2	P50416-1
	CPT1A	NM_001440358.1		c.2142+8C>T		splice_region intron	N/A	NP_001427287.1
	CPT1A	NM_001440359.1		c.2142+8C>T		splice_region intron	N/A	NP_001427288.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1A	ENST00000265641.10	TSL:1 MANE Select	c.2142+8C>T		splice_region intron	N/A	ENSP00000265641.4	P50416-1
	CPT1A	ENST00000376618.6	TSL:1	c.2142+8C>T		splice_region intron	N/A	ENSP00000365803.2	P50416-2
	CPT1A	ENST00000540367.5	TSL:1	c.2142+8C>T		splice_region intron	N/A	ENSP00000439084.1	P50416-2

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

GnomAD2 exomes AF: 0.000799 AC: 187 AN: 233998 AF XY: 0.00101

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 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

African (AFR) AF: 0.000663 AC: 22 AN: 33182

American (AMR) AF: 0.000300 AC: 13 AN: 43346

Ashkenazi Jewish (ASJ) AF: 0.000155 AC: 4 AN: 25808

East Asian (EAS) AF: 0.0000761 AC: 3 AN: 39406

South Asian (SAS) AF: 0.00205 AC: 173 AN: 84434

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52662

Middle Eastern (MID) AF: 0.0110 AC: 49 AN: 4442

European-Non Finnish (NFE) AF: 0.000429 AC: 473 AN: 1101516

Other (OTH) AF: 0.00124 AC: 74 AN: 59618

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

African (AFR) AF: 0.000144 AC: 6 AN: 41552

American (AMR) AF: 0.00118 AC: 18 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 67990

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000716 Hom.: 0

Bravo AF: 0.000559

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.34
DANN	Benign	0.46
PhyloP100		0.67
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs147563740; hg19: chr11-68527685;