9-104858586-C-T

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.656G>A(p.Arg219Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,856 control chromosomes in the GnomAD database, including 80,178 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 0.38 ( 13060 hom., cov: 33)

Exomes 𝑓: 0.29 ( 67118 hom. )

Consequence

ABCA1
NM_005502.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.545

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=1.2091895E-5).

BP6

Variant 9-104858586-C-T is Benign according to our data. Variant chr9-104858586-C-T is described in ClinVar as [Benign]. Clinvar id is 9506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104858586-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4 link	c.656G>A	p.Arg219Lys	missense_variant	Exon 7 of 50	ENST00000374736.8	NP_005493.2	O95477B7XCW9B2RUU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCA1	ENST00000374736.8 link	c.656G>A	p.Arg219Lys	missense_variant	Exon 7 of 50	1	NM_005502.4	ENSP00000363868.3	O95477
ABCA1	ENST00000678995.1 link	c.656G>A	p.Arg219Lys	missense_variant	Exon 7 of 50			ENSP00000504612.1	A0A7I2V5U0
ABCA1	ENST00000423487.6 link	c.656G>A	p.Arg219Lys	missense_variant	Exon 7 of 8	2		ENSP00000416623.2	B1AMI2

Frequencies

GnomAD3 genomes

AF:

0.384

AC:

58319

AN:

151970

Hom.:

13020

Cov.:

show subpopulations

Gnomad AFR

AF:

0.625

Gnomad AMI

AF:

0.447

Gnomad AMR

AF:

0.346

Gnomad ASJ

AF:

0.276

Gnomad EAS

AF:

0.427

Gnomad SAS

AF:

0.373

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.273

Gnomad OTH

AF:

0.377

GnomAD3 exomes

AF:

0.324

AC:

81377

AN:

251448

Hom.:

14428

AF XY:

0.320

AC XY:

43473

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.630

Gnomad AMR exome

AF:

0.325

Gnomad ASJ exome

AF:

0.281

Gnomad EAS exome

AF:

0.431

Gnomad SAS exome

AF:

0.368

Gnomad FIN exome

AF:

0.220

Gnomad NFE exome

AF:

0.274

Gnomad OTH exome

AF:

0.318

GnomAD4 exome

AF:

0.293

AC:

428401

AN:

1461766

Hom.:

67118

Cov.:

AF XY:

0.295

AC XY:

214422

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.647

Gnomad4 AMR exome

AF:

0.328

Gnomad4 ASJ exome

AF:

0.281

Gnomad4 EAS exome

AF:

0.472

Gnomad4 SAS exome

AF:

0.368

Gnomad4 FIN exome

AF:

0.220

Gnomad4 NFE exome

AF:

0.271

Gnomad4 OTH exome

AF:

0.319

GnomAD4 genome

AF:

0.384

AC:

58426

AN:

152090

Hom.:

13060

Cov.:

AF XY:

0.382

AC XY:

28416

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.626

Gnomad4 AMR

AF:

0.346

Gnomad4 ASJ

AF:

0.276

Gnomad4 EAS

AF:

0.427

Gnomad4 SAS

AF:

0.372

Gnomad4 FIN

AF:

0.222

Gnomad4 NFE

AF:

0.273

Gnomad4 OTH

AF:

0.382

Alfa

AF:

0.298

Hom.:

13809

Bravo

AF:

0.404

TwinsUK

AF:

0.259

AC:

959

ALSPAC

AF:

0.268

AC:

1032

ESP6500AA

AF:

0.606

AC:

2672

ESP6500EA

AF:

0.281

AC:

2420

ExAC

AF:

0.330

AC:

40042

Asia WGS

AF:

0.423

AC:

1471

AN:

3478

EpiCase

AF:

0.288

EpiControl

AF:

0.283

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

- -

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20170916, 21310416, 18927311, 12700893, 21643759, 20797885, 20346718, 21300560, 18621447, 19304534, 17407076, 11238261, 24157307, 26243156, 31006134, 25104170, 24466114, 27560308) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tangier disease

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Cardiovascular phenotype

Benign:1

Dec 11, 2018

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. -

RECLASSIFIED - ABCA1 POLYMORPHISM

Benign:1

Jan 01, 2006

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

0.072

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

6.2

DANN

Benign

0.83

DEOGEN2

Benign

0.24

T;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.37

T;T

MetaRNN

Benign

0.000012

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.11

N;.

PrimateAI

Benign

0.27

PROVEAN

Benign

0.010

N;N

REVEL

Benign

0.19

Sift

Benign

0.62

T;T

Sift4G

Benign

0.92

T;T

Polyphen

0.0

B;.

Vest4

0.041

MPC

0.18

ClinPred

0.00098

GERP RS

0.057

Varity_R

0.10

gMVP

0.089

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