NM_005502.4:c.254C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_005502.4(ABCA1):c.254C>T(p.Pro85Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,202 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P85S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

ABCA1
NM_005502.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 10.0

Publications

30 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 -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.013464153).

BP6

Variant 9-104884475-G-A is Benign according to our data. Variant chr9-104884475-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 364464.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00123 (187/152330) while in subpopulation SAS AF = 0.00207 (10/4828). AF 95% confidence interval is 0.0012. There are 0 homozygotes in GnomAd4. There are 101 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AD,AR gene

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.254C>T	p.Pro85Leu	missense	Exon 4 of 50	NP_005493.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.254C>T	p.Pro85Leu	missense	Exon 4 of 50	ENSP00000363868.3
ABCA1	ENST00000678995.1		c.254C>T	p.Pro85Leu	missense	Exon 4 of 50	ENSP00000504612.1
ABCA1	ENST00000423487.6	TSL:2	c.254C>T	p.Pro85Leu	missense	Exon 4 of 8	ENSP00000416623.2

Frequencies

GnomAD3 genomes

AF:

0.00123

AC:

187

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00536

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00143

AC:

359

AN:

251460

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00508

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00135

AC:

1969

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1006

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33478

American (AMR)

AF:

0.000425

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00155

AC:

134

AN:

86256

European-Finnish (FIN)

AF:

0.00485

AC:

259

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00133

AC:

1478

AN:

1111996

Other (OTH)

AF:

0.00109

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

110

219

329

438

548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.00123

AC:

187

AN:

152330

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

101

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41572

American (AMR)

AF:

0.000850

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00536

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00143

AC:

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00117

Hom.:

Bravo

AF:

0.000733

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00126

AC:

153

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.000771

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

ABCA1-related disorder (1)

Cardiovascular phenotype (1)

Hypoalphalipoproteinemia, primary, 1 (1)

not specified (1)

Tangier disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.013

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.3

PhyloP100

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.84

Sift

Benign

0.71

Sift4G

Benign

0.24

Polyphen

0.97

Vest4

0.59

MVP

0.99

MPC

0.49

ClinPred

0.062

GERP RS

5.4

Varity_R

0.52

gMVP

0.74

Mutation Taster

=29/71

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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