rs121912728

Positions:

• chr11-116836022-C-G
• chr11-116836022-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000039.3(APOA1):​c.590G>C​(p.Arg197Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: APOA1 NM_000039.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.226

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 11-116836022-C-G is Pathogenic according to our data. Variant chr11-116836022-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2137255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOA1	NM_000039.3	c.590G>C	p.Arg197Pro	missense_variant	4/4	ENST00000236850.5	NP_000030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOA1	ENST00000236850.5	c.590G>C	p.Arg197Pro	missense_variant	4/4	1	NM_000039.3	ENSP00000236850	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 20, 2022

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 197 of the APOA1 protein (p.Arg197Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyloidosis (PMID: 10198255, 32257250). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg173Pro. 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"). Experimental studies have shown that this missense change affects APOA1 function (PMID: 25950566). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T;T;T;T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.52	.;.;T;.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.5	M;M;.;M;M
MutationTaster	Benign	1.7e-10	A;A;A;A;A
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.028	D;D;D;D;D
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.96	P;P;.;P;P
Vest4		0.86
MutPred		0.60		Loss of MoRF binding (P = 0.007);Loss of MoRF binding (P = 0.007);.;Loss of MoRF binding (P = 0.007);Loss of MoRF binding (P = 0.007);
MVP		0.93
MPC		1.9
ClinPred		0.86	D
GERP RS		1.4
Varity_R		0.99
gMVP		0.84

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: rs121912728; hg19: chr11-116706738;