rs12718465

Variant names:

• chr11-116837020-C-T
• rs12718465
• NM_000039.3:c.181G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000039.3(APOA1):​c.181G>A​(p.Ala61Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,144 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (41 hom.)
• Consequence: APOA1 NM_000039.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.289
• Publications: 17 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033324957).
• BP6: Variant 11-116837020-C-T is Benign according to our data. Variant chr11-116837020-C-T is described in ClinVar as Benign. ClinVar VariationId is 302507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00135 (206/152330) while in subpopulation EAS AF = 0.0378 (196/5186). AF 95% confidence interval is 0.0335. There are 5 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

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.181G>A	p.Ala61Thr	missense	Exon 3 of 4	NP_000030.1
	APOA1	NM_001318017.2		c.181G>A	p.Ala61Thr	missense	Exon 3 of 4	NP_001304946.1
	APOA1	NM_001318018.2		c.181G>A	p.Ala61Thr	missense	Exon 3 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.181G>A	p.Ala61Thr	missense	Exon 3 of 4	ENSP00000236850.3
	APOA1	ENST00000375323.5	TSL:1	c.181G>A	p.Ala61Thr	missense	Exon 2 of 3	ENSP00000364472.1
	APOA1	ENST00000359492.6	TSL:2	c.181G>A	p.Ala61Thr	missense	Exon 3 of 4	ENSP00000352471.2

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152212 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0373

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00296 AC: 744 AN: 251256 AF XY: 0.00272

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00134 AC: 1958 AN: 1461814 Hom.: 41 Cov.: 36 AF XY: 0.00133 AC XY: 964 AN XY: 727204

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0445 AC: 1766 AN: 39698

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1112008

Other (OTH) AF: 0.00233 AC: 141 AN: 60392

GnomAD4 genome AF: 0.00135 AC: 206 AN: 152330 Hom.: 5 Cov.: 33 AF XY: 0.00145 AC XY: 108 AN XY: 74488

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.000392 AC: 6 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0378 AC: 196 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00123 Hom.: 6

Bravo AF: 0.00150

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00284 AC: 345

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial visceral amyloidosis, Ostertag type (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypoalphalipoproteinemia, primary, 1 (1)
-	-	1	Hypoalphalipoproteinemia, primary, 2 (1)
-	-	1	Hypoalphalipoproteinemia, primary, 2, intermediate (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	10
DANN	Benign	0.75
DEOGEN2	Benign	0.093	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.29
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.042
Sift	Benign	0.67	T
Sift4G	Benign	1.0	T
Polyphen		0.021	B
Vest4		0.25
MVP		0.63
MPC		0.59
ClinPred		0.0023	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.090
gMVP		0.11
Mutation Taster		=97/3	polymorphism

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: rs12718465; hg19: chr11-116707736; COSMIC: COSV105846985; COSMIC: COSV105846985;