9-104800523-T-C

Position:

chr9-104800523-T-C

Variant summary

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

The NM_005502.4(ABCA1):c.4760A>G(p.Lys1587Arg) variant causes a missense change. The variant allele was found at a frequency of 0.725 in 1,612,774 control chromosomes in the GnomAD database, including 437,586 homozygotes. In-silico tool predicts 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. K1587Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.60 ( 32188 hom., cov: 32)

Exomes 𝑓: 0.74 ( 405398 hom. )

Consequence

ABCA1
NM_005502.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.95

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=1.7720122E-6).

BP6

Variant 9-104800523-T-C is Benign according to our data. Variant chr9-104800523-T-C is described in ClinVar as [Benign]. Clinvar id is 364398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104800523-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA1	NM_005502.4 linkuse as main transcript	c.4760A>G	p.Lys1587Arg	missense_variant	35/50	ENST00000374736.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA1	ENST00000374736.8 linkuse as main transcript	c.4760A>G	p.Lys1587Arg	missense_variant	35/50	1	NM_005502.4	P1
ABCA1	ENST00000678995.1 linkuse as main transcript	c.4766A>G	p.Lys1589Arg	missense_variant	35/50

Frequencies

GnomAD3 genomes

AF:

0.604

AC:

91783

AN:

151968

Hom.:

32186

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.765

Gnomad AMR

AF:

0.725

Gnomad ASJ

AF:

0.746

Gnomad EAS

AF:

0.602

Gnomad SAS

AF:

0.641

Gnomad FIN

AF:

0.845

Gnomad MID

AF:

0.541

Gnomad NFE

AF:

0.761

Gnomad OTH

AF:

0.628

GnomAD3 exomes

AF:

0.707

AC:

177856

AN:

251394

Hom.:

65969

AF XY:

0.710

AC XY:

96531

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.208

Gnomad AMR exome

AF:

0.790

Gnomad ASJ exome

AF:

0.744

Gnomad EAS exome

AF:

0.591

Gnomad SAS exome

AF:

0.642

Gnomad FIN exome

AF:

0.843

Gnomad NFE exome

AF:

0.760

Gnomad OTH exome

AF:

0.726

GnomAD4 exome

AF:

0.738

AC:

1078212

AN:

1460688

Hom.:

405398

Cov.:

AF XY:

0.737

AC XY:

535261

AN XY:

726734

show subpopulations

Gnomad4 AFR exome

AF:

0.195

Gnomad4 AMR exome

AF:

0.784

Gnomad4 ASJ exome

AF:

0.748

Gnomad4 EAS exome

AF:

0.611

Gnomad4 SAS exome

AF:

0.640

Gnomad4 FIN exome

AF:

0.837

Gnomad4 NFE exome

AF:

0.763

Gnomad4 OTH exome

AF:

0.701

GnomAD4 genome

AF:

0.604

AC:

91810

AN:

152086

Hom.:

32188

Cov.:

AF XY:

0.612

AC XY:

45483

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.220

Gnomad4 AMR

AF:

0.725

Gnomad4 ASJ

AF:

0.746

Gnomad4 EAS

AF:

0.601

Gnomad4 SAS

AF:

0.641

Gnomad4 FIN

AF:

0.845

Gnomad4 NFE

AF:

0.761

Gnomad4 OTH

AF:

0.629

Alfa

AF:

0.721

Hom.:

84986

Bravo

AF:

0.580

TwinsUK

AF:

0.764

AC:

2834

ALSPAC

AF:

0.773

AC:

2981

ESP6500AA

AF:

0.243

AC:

1069

ESP6500EA

AF:

0.760

AC:

6540

ExAC

AF:

0.693

AC:

84189

Asia WGS

AF:

0.581

AC:

2025

AN:

3478

EpiCase

AF:

0.750

EpiControl

AF:

0.750

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	This variant is associated with the following publications: (PMID: 29083407, 28008009, 15520867, 20346718, 22929031) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Tangier disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

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. -

Hypoalphalipoproteinemia, primary, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Benign

0.90

DEOGEN2

Benign

0.32

Eigen

Benign

-0.22

Eigen_PC

Benign

0.045

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0000018

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

MutationTaster

Benign

0.00014

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.22

REVEL

Uncertain

0.36

Sift

Benign

1.0

Sift4G

Benign

0.80

Polyphen

0.018

Vest4

0.22

MPC

0.34

ClinPred

0.013

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.46

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