11-116836017-C-T

Variant names:

• chr11-116836017-C-T
• rs121912730
• NM_000039.3:c.595G>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.595G>A​(p.Ala199Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,607,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 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. A199P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: APOA1 NM_000039.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.535

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, 7 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 chr11-116836017-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 17934.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.092250735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOA1	NM_000039.3	c.595G>A	p.Ala199Thr	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.595G>A	p.Ala199Thr	missense_variant	Exon 4 of 4	1	NM_000039.3	ENSP00000236850.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000828 AC: 2 AN: 241532 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

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: 0.00000206 AC: 3 AN: 1454860 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724036

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33458

Gnomad4 AMR exome AF: 0.0000672 AC: 3 AN: 44672

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26086

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39686

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86184

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 47160

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1111634

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60298

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.0000482 AC: 0.000048223 AN: 0.000048223

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.090	T;T;T;T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.65	.;.;T;.;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.092	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.8	L;L;.;L;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.060	N;N;N;N;N
REVEL	Benign	0.068
Sift	Benign	0.34	T;T;T;T;T
Sift4G	Benign	0.45	T;T;T;T;T
Polyphen		0.0030	B;B;.;B;B
Vest4		0.077
MutPred		0.49		Gain of phosphorylation at A199 (P = 0.0111);Gain of phosphorylation at A199 (P = 0.0111);.;Gain of phosphorylation at A199 (P = 0.0111);Gain of phosphorylation at A199 (P = 0.0111);
MVP		0.76
MPC		0.64
ClinPred		0.036	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.19
gMVP		0.11
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121912730; hg19: chr11-116706733;