rs75677837

Variant names:

• chr11-68793312-C-T
• rs75677837
• NM_001876.4:c.967+3G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BA1

The NM_001876.4(CPT1A):​c.967+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,607,360 control chromosomes in the GnomAD database, including 638 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (59 hom., cov: 31)
  • Exomes 𝑓: 0.020 (579 hom.)
• Consequence: CPT1A NM_001876.4 splice_region, intron
• Scores: Splicing: ADA: 0.004882
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.19
• Publications: 7 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, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18).
• BP6: Variant 11-68793312-C-T is Benign according to our data. Variant chr11-68793312-C-T is described in ClinVar as Benign. ClinVar VariationId is 93978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0714 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1A	NM_001876.4	MANE Select	c.967+3G>A		splice_region intron	N/A	NP_001867.2
	CPT1A	NM_001440358.1		c.967+3G>A		splice_region intron	N/A	NP_001427287.1
	CPT1A	NM_001440359.1		c.967+3G>A		splice_region intron	N/A	NP_001427288.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1A	ENST00000265641.10	TSL:1 MANE Select	c.967+3G>A		splice_region intron	N/A	ENSP00000265641.4
	CPT1A	ENST00000376618.6	TSL:1	c.967+3G>A		splice_region intron	N/A	ENSP00000365803.2
	CPT1A	ENST00000540367.5	TSL:1	c.967+3G>A		splice_region intron	N/A	ENSP00000439084.1

Frequencies

GnomAD3 genomes AF: 0.0190 AC: 2884 AN: 152172 Hom.: 59 Cov.: 31

Gnomad AFR AF: 0.00666

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0388

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.0773

Gnomad SAS AF: 0.0623

Gnomad FIN AF: 0.0163

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0326 AC: 8034 AN: 246402 AF XY: 0.0329

Gnomad AFR exome AF: 0.00609

Gnomad AMR exome AF: 0.0624

Gnomad ASJ exome AF: 0.0279

Gnomad EAS exome AF: 0.0764

Gnomad FIN exome AF: 0.0185

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0328

GnomAD4 exome AF: 0.0197 AC: 28635 AN: 1455070 Hom.: 579 Cov.: 29 AF XY: 0.0209 AC XY: 15108 AN XY: 723630

African (AFR) AF: 0.00531 AC: 177 AN: 33334

American (AMR) AF: 0.0610 AC: 2702 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 711 AN: 25938

East Asian (EAS) AF: 0.0751 AC: 2975 AN: 39598

South Asian (SAS) AF: 0.0596 AC: 5096 AN: 85478

European-Finnish (FIN) AF: 0.0187 AC: 998 AN: 53256

Middle Eastern (MID) AF: 0.0639 AC: 300 AN: 4694

European-Non Finnish (NFE) AF: 0.0127 AC: 14081 AN: 1108398

Other (OTH) AF: 0.0265 AC: 1595 AN: 60088

GnomAD4 genome AF: 0.0190 AC: 2886 AN: 152290 Hom.: 59 Cov.: 31 AF XY: 0.0199 AC XY: 1485 AN XY: 74466

African (AFR) AF: 0.00664 AC: 276 AN: 41556

American (AMR) AF: 0.0388 AC: 594 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3470

East Asian (EAS) AF: 0.0776 AC: 402 AN: 5178

South Asian (SAS) AF: 0.0621 AC: 300 AN: 4830

European-Finnish (FIN) AF: 0.0163 AC: 173 AN: 10616

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0140 AC: 952 AN: 68030

Other (OTH) AF: 0.0303 AC: 64 AN: 2114

Alfa AF: 0.0158 Hom.: 11

Bravo AF: 0.0208

Asia WGS AF: 0.0520 AC: 181 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Carnitine palmitoyl transferase 1A deficiency (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Benign	0.97
PhyloP100		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=81/19	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0049
dbscSNV1_RF	Benign	0.046
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: rs75677837; hg19: chr11-68560780;