rs2066715

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005502.4(ABCA1):c.2473G>A(p.Val825Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0677 in 1,614,094 control chromosomes in the GnomAD database, including 6,225 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 0.059 ( 634 hom., cov: 33)

Exomes 𝑓: 0.069 ( 5591 hom. )

Consequence

ABCA1
NM_005502.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.67

Publications

90 publications found

Variant links:

Genes affected

ABCA1 (HGNC:29): (ATP binding cassette subfamily A member 1) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. With cholesterol as its substrate, this protein functions as a cholesteral efflux pump in the cellular lipid removal pathway. Mutations in both alleles of this gene cause Tangier disease and familial high-density lipoprotein (HDL) deficiency. [provided by RefSeq, Sep 2019]

ABCA1 Gene-Disease associations (from GenCC):

hypoalphalipoproteinemia, primary, 1
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Tangier disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
apolipoprotein A-I deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ABCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036743283).

BP6

Variant 9-104825752-C-T is Benign according to our data. Variant chr9-104825752-C-T is described in ClinVar as Benign. ClinVar VariationId is 364428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005502.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.2473G>A	p.Val825Ile	missense	Exon 17 of 50	NP_005493.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.2473G>A	p.Val825Ile	missense	Exon 17 of 50	ENSP00000363868.3	O95477
ABCA1	ENST00000678995.1		c.2473G>A	p.Val825Ile	missense	Exon 17 of 50	ENSP00000504612.1	A0A7I2V5U0
ABCA1	ENST00000494467.1	TSL:3	n.646G>A		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.0593

AC:

9022

AN:

152136

Hom.:

633

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0154

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0621

Gnomad ASJ

AF:

0.0550

Gnomad EAS

AF:

0.409

Gnomad SAS

AF:

0.0607

Gnomad FIN

AF:

0.0556

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0603

Gnomad OTH

AF:

0.0603

GnomAD2 exomes

AF:

0.0821

AC:

20641

AN:

251464

AF XY:

0.0799

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.0593

Gnomad ASJ exome

AF:

0.0592

Gnomad EAS exome

AF:

0.426

Gnomad FIN exome

AF:

0.0512

Gnomad NFE exome

AF:

0.0603

Gnomad OTH exome

AF:

0.0710

GnomAD4 exome

AF:

0.0686

AC:

100257

AN:

1461840

Hom.:

5591

Cov.:

AF XY:

0.0683

AC XY:

49666

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0113

AC:

378

AN:

33480

American (AMR)

AF:

0.0591

AC:

2641

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0607

AC:

1586

AN:

26136

East Asian (EAS)

AF:

0.379

AC:

15047

AN:

39698

South Asian (SAS)

AF:

0.0536

AC:

4626

AN:

86256

European-Finnish (FIN)

AF:

0.0495

AC:

2642

AN:

53420

Middle Eastern (MID)

AF:

0.0356

AC:

205

AN:

5766

European-Non Finnish (NFE)

AF:

0.0619

AC:

68823

AN:

1111966

Other (OTH)

AF:

0.0713

AC:

4309

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

5627

11255

16882

22510

28137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2744

5488

8232

10976

13720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0593

AC:

9031

AN:

152254

Hom.:

634

Cov.:

AF XY:

0.0612

AC XY:

4557

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0155

AC:

646

AN:

41564

American (AMR)

AF:

0.0623

AC:

954

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0550

AC:

191

AN:

3472

East Asian (EAS)

AF:

0.409

AC:

2106

AN:

5154

South Asian (SAS)

AF:

0.0612

AC:

295

AN:

4820

European-Finnish (FIN)

AF:

0.0556

AC:

589

AN:

10598

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0603

AC:

4102

AN:

68024

Other (OTH)

AF:

0.0601

AC:

127

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

403

807

1210

1614

2017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0637

Hom.:

1935

Bravo

AF:

0.0601

TwinsUK

AF:

0.0604

AC:

224

ALSPAC

AF:

0.0641

AC:

247

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.0627

AC:

539

ExAC

AF:

0.0804

AC:

9766

Asia WGS

AF:

0.202

AC:

701

AN:

3478

EpiCase

AF:

0.0558

EpiControl

AF:

0.0614

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Cardiovascular phenotype (1)

Hypoalphalipoproteinemia, primary, 1 (1)

Tangier disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.10

DEOGEN2

Benign

0.31

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.51

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.86

MetaRNN

Benign

0.0037

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

PhyloP100

1.7

PrimateAI

Benign

0.34

PROVEAN

Benign

0.22

REVEL

Benign

0.20

Sift

Benign

0.86

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.053

MPC

0.14

ClinPred

0.0051

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.22

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over