rs28931574

Variant names:

• chr11-116837053-C-G
• rs28931574
• NM_000039.3:c.148G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-116837053-C-G
• chr11-116837053-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000039.3(APOA1):​c.148G>C​(p.Gly50Arg) 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, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.29

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 11-116837053-C-G is Pathogenic according to our data. Variant chr11-116837053-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 17917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA1	NM_000039.3	c.148G>C	p.Gly50Arg	missense_variant	Exon 3 of 4	ENST00000236850.5	NP_000030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA1	ENST00000236850.5	c.148G>C	p.Gly50Arg	missense_variant	Exon 3 of 4	1	NM_000039.3	ENSP00000236850.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial amyloid polyneuropathy, Iowa type Pathogenic:1

Oct 01, 1990

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Mar 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with autosomal dominant systemic amyloidosis (PMID: 2123470). It has also been observed to segregate with disease in related individuals. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 50 of the APOA1 protein (p.Gly50Arg). This variant is not present in population databases (gnomAD no frequency). This variant is also known as glycine to arginine-26 substitution, ApoA-I Iowa, or G26R. ClinVar contains an entry for this variant (Variation ID: 17917). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt APOA1 protein function. Experimental studies have shown that this missense change affects APOA1 function (PMID: 17665932, 21296086, 22952757, 23233678, 27464946). For these reasons, this variant has been classified as Pathogenic. -

Familial amyloid polyneuropathy, Iowa type;C5551172:Hypoalphalipoproteinemia, primary, 2;C5677030:Hypoalphalipoproteinemia, primary, 2, intermediate Pathogenic:1

Feb 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial visceral amyloidosis, Ostertag type Pathogenic:1

Dec 06, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in APOA1 is predicted to replace glycine with arginine at codon 50, p.(Gly50Arg). Note, this variant is also referred to in the literature as p.(Gly26Arg). This glycine residue is critical for β-structure termination (PMID: 17665932, 27464946) and is highly conserved (100 vertebrate, Multiz Alignment). There is a large physicochemical difference between glycine and arginine. This variant is absent from the population database gnomAD v4.1. This variant has been reported in several probands with apolipoprotein-A1 familial amyloid polyneuropathy, including in one large multi-generational kindred in which the variant segregates with disease in the affected family members (PMID: 33502644, 2123470, 3142462, 4304452). Functional studies suggest this variant leads to decreased lipid binding function and promotion of amyloid formation (PMID: 17665932, 21296086, 23233678). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.7). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as PATHOGENIC. Following criteria are met: PM1, PM2_Supporting, PP1_Moderate, PP3, PS3_Supporting, PS4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	19
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D;D;D;D
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	.;.;.;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	2.9	M;M;M;M
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.82
MutPred		0.87		Gain of methylation at K47 (P = 0.0469);Gain of methylation at K47 (P = 0.0469);Gain of methylation at K47 (P = 0.0469);Gain of methylation at K47 (P = 0.0469);
MVP		0.87
MPC		1.7
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.87
gMVP		0.83

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: rs28931574; hg19: chr11-116707769;