11-116835821-A-G

Variant names:

• chr11-116835821-A-G
• NM_000039.3:c.791T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000039.3(APOA1):​c.791T>C​(p.Leu264Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APOA1 NM_000039.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.94

Genes affected

APOA1 (HGNC:600): (apolipoprotein A1) This gene encodes apolipoprotein A-I, which is the major protein component of high density lipoprotein (HDL) in plasma. The encoded preproprotein is proteolytically processed to generate the mature protein, which promotes cholesterol efflux from tissues to the liver for excretion, and is a cofactor for lecithin cholesterolacyltransferase (LCAT), an enzyme responsible for the formation of most plasma cholesteryl esters. This gene is closely linked with two other apolipoprotein genes on chromosome 11. Defects in this gene are associated with HDL deficiencies, including Tangier disease, and with systemic non-neuropathic amyloidosis. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA1	NM_000039.3	c.791T>C	p.Leu264Pro	missense_variant	Exon 4 of 4	ENST00000236850.5	NP_000030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA1	ENST00000236850.5	c.791T>C	p.Leu264Pro	missense_variant	Exon 4 of 4	1	NM_000039.3	ENSP00000236850.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460730 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L264P variant (also known as c.791T>C), located in coding exon 3 of the APOA1 gene, results from a T to C substitution at nucleotide position 791. The leucine at codon 264 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;T;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.48	.;.;T;.;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.8	M;M;.;M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.62
MutPred		0.47		Gain of disorder (P = 0.0336);Gain of disorder (P = 0.0336);.;Gain of disorder (P = 0.0336);Gain of disorder (P = 0.0336);
MVP		0.96
MPC		2.0
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.86
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-116706537;