rs2066714

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005502.4(ABCA1):c.2649A>G(p.Ile883Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,613,862 control chromosomes in the GnomAD database, including 33,696 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 7196 hom., cov: 32)

Exomes 𝑓: 0.16 ( 26500 hom. )

Consequence

ABCA1
NM_005502.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.873

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.671956E-6).

BP6

Variant 9-104824472-T-C is Benign according to our data. Variant chr9-104824472-T-C is described in ClinVar as [Benign]. Clinvar id is 364426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104824472-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4 link	c.2649A>G	p.Ile883Met	missense_variant	Exon 18 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.2649A>G	p.Ile883Met	missense_variant	Exon 18 of 50	1	NM_005502.4	ENSP00000363868.3		O95477
ABCA1	ENST00000678995.1 link	c.2649A>G	p.Ile883Met	missense_variant	Exon 18 of 50			ENSP00000504612.1		A0A7I2V5U0

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38593

AN:

151990

Hom.:

7177

Cov.:

show subpopulations

Gnomad AFR

AF:

0.477

Gnomad AMI

AF:

0.0923

Gnomad AMR

AF:

0.219

Gnomad ASJ

AF:

0.188

Gnomad EAS

AF:

0.694

Gnomad SAS

AF:

0.160

Gnomad FIN

AF:

0.104

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.128

Gnomad OTH

AF:

0.248

GnomAD3 exomes

AF:

0.211

AC:

53126

AN:

251362

Hom.:

9257

AF XY:

0.198

AC XY:

26918

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.480

Gnomad AMR exome

AF:

0.223

Gnomad ASJ exome

AF:

0.191

Gnomad EAS exome

AF:

0.718

Gnomad SAS exome

AF:

0.141

Gnomad FIN exome

AF:

0.101

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.195

GnomAD4 exome

AF:

0.158

AC:

230954

AN:

1461756

Hom.:

26500

Cov.:

AF XY:

0.156

AC XY:

113725

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.492

Gnomad4 AMR exome

AF:

0.223

Gnomad4 ASJ exome

AF:

0.198

Gnomad4 EAS exome

AF:

0.663

Gnomad4 SAS exome

AF:

0.148

Gnomad4 FIN exome

AF:

0.0973

Gnomad4 NFE exome

AF:

0.128

Gnomad4 OTH exome

AF:

0.193

GnomAD4 genome

AF:

0.254

AC:

38670

AN:

152106

Hom.:

7196

Cov.:

AF XY:

0.253

AC XY:

18846

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.477

Gnomad4 AMR

AF:

0.220

Gnomad4 ASJ

AF:

0.188

Gnomad4 EAS

AF:

0.694

Gnomad4 SAS

AF:

0.160

Gnomad4 FIN

AF:

0.104

Gnomad4 NFE

AF:

0.128

Gnomad4 OTH

AF:

0.252

Alfa

AF:

0.172

Hom.:

6478

Bravo

AF:

0.281

TwinsUK

AF:

0.121

AC:

449

ALSPAC

AF:

0.123

AC:

473

ESP6500AA

AF:

0.464

AC:

2045

ESP6500EA

AF:

0.134

AC:

1154

ExAC

AF:

0.213

AC:

25882

Asia WGS

AF:

0.401

AC:

1394

AN:

3478

EpiCase

AF:

0.132

EpiControl

AF:

0.139

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24466114, 31006134, 26243156, 27884173, 10431237, 21300560, 11238261, 17951323, 17923263) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 20, 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). 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. -

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). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.79

DANN

Benign

0.28

DEOGEN2

Benign

0.28

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.028

MetaRNN

Benign

0.0000027

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.090

REVEL

Benign

0.16

Sift

Benign

0.15

Sift4G

Benign

0.11

Polyphen

0.0020

Vest4

0.022

MPC

1.1

ClinPred

0.00040

GERP RS

0.16

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.059

gMVP

0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over