rs121912719

chr11-116836112-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_000039.3(APOA1):c.500C>G(p.Pro167Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,459,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: APOA1 NM_000039.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.51

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 4 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, 14 uncertain in NM_000039.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOA1	NM_000039.3	c.500C>G	p.Pro167Arg	missense_variant	4/4	ENST00000236850.5
APOA1-AS	NR_126362.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOA1	ENST00000236850.5	c.500C>G	p.Pro167Arg	missense_variant	4/4	1	NM_000039.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1459378 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726094

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: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

APOLIPOPROTEIN A-I (GIESSEN) Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 15, 1984

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 17, 2021

Experimental studies have shown that this missense change affects APOA1 function (PMID: 6489332). 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. 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"). ClinVar contains an entry for this variant (Variation ID: 17910). This variant is also known as Pro143Arg, Apo A-I Giessen. This missense change has been observed in individual(s) with APOA1-related conditions (PMID: 6489332). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 167 of the APOA1 protein (p.Pro167Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D;T;D;D
Eigen	Benign	0.063
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.50	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.8	M;M;.;M;M
MutationTaster	Benign	0.00017	A;A;A;A;A
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.7	D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D;D
Polyphen		0.98	D;D;.;D;D
Vest4		0.64
MutPred		0.57		Gain of MoRF binding (P = 3e-04);Gain of MoRF binding (P = 3e-04);.;Gain of MoRF binding (P = 3e-04);Gain of MoRF binding (P = 3e-04);
MVP		0.93
MPC		1.6
ClinPred		0.98	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs121912719; hg19: chr11-116706828;