rs28931573

Positions:

• chr11-116836023-G-A
• chr11-116836023-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000039.3(APOA1):​c.589C>T​(p.Arg197Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: APOA1 NM_000039.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.320

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-116836023-G-A is Pathogenic according to our data. Variant chr11-116836023-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17909.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOA1	NM_000039.3	c.589C>T	p.Arg197Cys	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.589C>T	p.Arg197Cys	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: no assertion criteria provided

Submissions by phenotype

APOLIPOPROTEIN A-I (MILANO) Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 05, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;T;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.029	N
LIST_S2	Uncertain	0.88	.;.;D;.;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.65	D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.5	M;M;.;M;M
MutationTaster	Benign	2.4e-8	A;A;A;A;A
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.13
MutPred		0.59		Loss of MoRF binding (P = 0.011);Loss of MoRF binding (P = 0.011);.;Loss of MoRF binding (P = 0.011);Loss of MoRF binding (P = 0.011);
MVP		0.89
MPC		1.8
ClinPred		0.98	D
GERP RS		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.50

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: rs28931573; hg19: chr11-116706739;