NM_000039.3:c.220T>C

Variant names:

• chr11-116836392-A-G
• rs121912726
• NM_000039.3:c.220T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000039.3(APOA1):​c.220T>C​(p.Trp74Arg) 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:2
• Conservation: PhyloP100: 3.22

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 11-116836392-A-G is Pathogenic according to our data. Variant chr11-116836392-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 17928.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA1	NM_000039.3	c.220T>C	p.Trp74Arg	missense_variant	Exon 4 of 4	ENST00000236850.5	NP_000030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOA1	ENST00000236850.5	c.220T>C	p.Trp74Arg	missense_variant	Exon 4 of 4	1	NM_000039.3	ENSP00000236850.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial amyloid polyneuropathy, Iowa type Pathogenic:1

Jun 15, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 25, 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 individuals with autosomal dominant systemic amyloidosis (PMID: 7493166, 26299174, 27240838, 28953655, 31870425). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 74 of the APOA1 protein (p.Trp74Arg). This variant is not present in population databases (gnomAD no frequency). This variant is also known as p.Trp50Arg. ClinVar contains an entry for this variant (Variation ID: 17928). 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: 21296086, 24702826). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;T;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.68	.;.;T;.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.7	M;M;.;M;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.016	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		0.97	D;D;.;D;D
Vest4		0.78
MutPred		0.78		Gain of disorder (P = 0.0019);Gain of disorder (P = 0.0019);.;Gain of disorder (P = 0.0019);Gain of disorder (P = 0.0019);
MVP		0.88
MPC		2.1
ClinPred		0.97	D
GERP RS		2.6
Varity_R		0.93
gMVP		0.66

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: rs121912726; hg19: chr11-116707108;