11-116835871-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000039.3(APOA1):c.741G>C(p.Glu247Asp) 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 1,460,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APOA1 NM_000039.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOA1	NM_000039.3	c.741G>C	p.Glu247Asp	missense_variant	4/4	ENST00000236850.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOA1	ENST00000236850.5	c.741G>C	p.Glu247Asp	missense_variant	4/4	1	NM_000039.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460862 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726758

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 12, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 247 of the APOA1 protein (p.Glu247Asp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APOA1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;T;T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.72	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.5	M;M;.;M;M
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.9	N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.19	T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.024	B;B;.;B;B
Vest4		0.34
MutPred		0.92		Loss of ubiquitination at K250 (P = 0.0699);Loss of ubiquitination at K250 (P = 0.0699);.;Loss of ubiquitination at K250 (P = 0.0699);Loss of ubiquitination at K250 (P = 0.0699);
MVP		0.93
MPC		1.5
ClinPred		0.86	D
GERP RS		0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.44

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: chr11-116706587;