rs33918808

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.3516G>C(p.Glu1172Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,614,132 control chromosomes in the GnomAD database, including 1,919 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1172G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.069 ( 686 hom., cov: 32)

Exomes 𝑓: 0.032 ( 1233 hom. )

Consequence

ABCA1
NM_005502.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.898

Publications

39 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
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=0.0016642511).

BP6

Variant 9-104817351-C-G is Benign according to our data. Variant chr9-104817351-C-G is described in ClinVar as Benign. ClinVar VariationId is 364416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4 link	c.3516G>C	p.Glu1172Asp	missense_variant	Exon 24 of 50	ENST00000374736.8	NP_005493.2	O95477B7XCW9B2RUU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8 link	c.3516G>C	p.Glu1172Asp	missense_variant	Exon 24 of 50	1	NM_005502.4	ENSP00000363868.3		O95477
ABCA1	ENST00000678995.1 link	c.3463-47G>C		intron_variant	Intron 23 of 49			ENSP00000504612.1		A0A7I2V5U0

Frequencies

GnomAD3 genomes

AF:

0.0687

AC:

10455

AN:

152150

Hom.:

686

Cov.:

show subpopulations

Gnomad AFR

AF:

0.173

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0393

Gnomad ASJ

AF:

0.0415

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0294

Gnomad OTH

AF:

0.0631

GnomAD2 exomes

AF:

0.0348

AC:

8752

AN:

251472

AF XY:

0.0320

show subpopulations

Gnomad AFR exome

AF:

0.175

Gnomad AMR exome

AF:

0.0202

Gnomad ASJ exome

AF:

0.0379

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0250

Gnomad NFE exome

AF:

0.0291

Gnomad OTH exome

AF:

0.0353

GnomAD4 exome

AF:

0.0323

AC:

47163

AN:

1461864

Hom.:

1233

Cov.:

AF XY:

0.0315

AC XY:

22912

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.177

AC:

5924

AN:

33476

American (AMR)

AF:

0.0217

AC:

969

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0412

AC:

1077

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0223

AC:

1923

AN:

86254

European-Finnish (FIN)

AF:

0.0247

AC:

1321

AN:

53414

Middle Eastern (MID)

AF:

0.0678

AC:

391

AN:

5768

European-Non Finnish (NFE)

AF:

0.0298

AC:

33170

AN:

1111998

Other (OTH)

AF:

0.0395

AC:

2385

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

2804

5607

8411

11214

14018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1338

2676

4014

5352

6690

<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:

0.0688

AC:

10471

AN:

152268

Hom.:

686

Cov.:

AF XY:

0.0667

AC XY:

4963

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.173

AC:

7196

AN:

41520

American (AMR)

AF:

0.0392

AC:

600

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0415

AC:

144

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.0168

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0271

AC:

288

AN:

10616

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0294

AC:

1998

AN:

68028

Other (OTH)

AF:

0.0624

AC:

132

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

462

925

1387

1850

2312

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

216

324

432

540

<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:

0.0345

Hom.:

126

Bravo

AF:

0.0735

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0231

AC:

ESP6500AA

AF:

0.161

AC:

710

ESP6500EA

AF:

0.0317

AC:

273

ExAC

AF:

0.0382

AC:

4636

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0322

EpiControl

AF:

0.0298

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 01, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11257261, 24503134, 20880529) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCA1-related disorder

Benign:1

Mar 01, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Apr 30, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Tangier disease

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Hypoalphalipoproteinemia, primary, 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.30

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.7

PhyloP100

0.90

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.49

REVEL

Uncertain

0.33

Sift

Benign

0.32

Sift4G

Benign

0.52

Polyphen

0.0010

Vest4

0.23

MutPred

0.25

Loss of sheet (P = 0.0315);

MPC

0.34

ClinPred

0.0074

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.45

Mutation Taster

=91/9

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over