11-116836023-G-T

Variant names:

• chr11-116836023-G-T
• rs28931573
• NM_000039.3:c.589C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000039.3(APOA1):​c.589C>A​(p.Arg197Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R197C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: APOA1 NM_000039.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.320
• Publications: 6 publications found

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

Our verdict: Uncertain_significance. The variant received 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 1 benign, 9 uncertain in NM_000039.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-116836023-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17909.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10646033).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000039.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA1	NM_000039.3	MANE Select	c.589C>A	p.Arg197Ser	missense	Exon 4 of 4	NP_000030.1
	APOA1	NM_001318017.2		c.589C>A	p.Arg197Ser	missense	Exon 4 of 4	NP_001304946.1
	APOA1	NM_001318018.2		c.589C>A	p.Arg197Ser	missense	Exon 4 of 4	NP_001304947.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOA1	ENST00000236850.5	TSL:1 MANE Select	c.589C>A	p.Arg197Ser	missense	Exon 4 of 4	ENSP00000236850.3
	APOA1	ENST00000375323.5	TSL:1	c.589C>A	p.Arg197Ser	missense	Exon 3 of 3	ENSP00000364472.1
	APOA1	ENST00000359492.6	TSL:2	c.589C>A	p.Arg197Ser	missense	Exon 4 of 4	ENSP00000352471.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240396 AF XY: 0.00000760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454270 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723768

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111548

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.32
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.087
Sift	Benign	0.38	T
Sift4G	Benign	0.58	T
Polyphen		0.057	B
Vest4		0.20
MutPred		0.50		Loss of MoRF binding (P = 0.0283)
MVP		0.85
MPC		0.98
ClinPred		0.060	T
GERP RS		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.76
gMVP		0.52
Mutation Taster		=26/74	disease causing

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

Other links and lift over

dbSNP: rs28931573; hg19: chr11-116706739;