11-116836121-T-C

Position:

• chr11-116836121-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000039.3(APOA1):​c.491A>G​(p.Lys164Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K164K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: APOA1 NM_000039.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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]

APOA1-AS (HGNC:40079): (APOA1 antisense RNA)

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_000039.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34869495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOA1	NM_000039.3	c.491A>G	p.Lys164Arg	missense_variant	4/4	ENST00000236850.5
APOA1-AS	NR_126362.1	n.5T>C		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOA1	ENST00000236850.5	c.491A>G	p.Lys164Arg	missense_variant	4/4	1	NM_000039.3	P1
APOA1-AS	ENST00000669664.1			upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

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

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

APOA1: PM2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.71	.;.;T;.;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Uncertain	-0.099	T
MutationAssessor	Uncertain	2.4	M;M;.;M;M
MutationTaster	Benign	0.57	D;D;D;D;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.10	T;T;T;T;T
Sift4G	Benign	0.089	T;T;T;T;T
Polyphen		0.44	B;B;.;B;B
Vest4		0.23
MutPred		0.41		Loss of ubiquitination at K164 (P = 0.0019);Loss of ubiquitination at K164 (P = 0.0019);.;Loss of ubiquitination at K164 (P = 0.0019);Loss of ubiquitination at K164 (P = 0.0019);
MVP		0.93
MPC		0.86
ClinPred		0.67	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.37

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: chr11-116706837;