rs142807525

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PVS1_SupportingBP6_Very_StrongBS1BS2

The NM_212533.3(ABCA2):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,328,010 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 55 hom., cov: 33)

Exomes 𝑓: 0.00097 ( 27 hom. )

Consequence

ABCA2
NM_212533.3 start_lost

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.67

Publications

2 publications found

Variant links:

Genes affected

ABCA2 (HGNC:32): (ATP binding cassette subfamily A member 2) 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. This protein is highly expressed in brain tissue and may play a role in macrophage lipid metabolism and neural development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ABCA2 links:

LINC02908 (HGNC:31426): (long intergenic non-protein coding RNA 2908)

LINC02908 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 101 codons. Genomic position: 137023005. Lost 0.041 part of the original CDS.

BP6

Variant 9-137028872-T-C is Benign according to our data. Variant chr9-137028872-T-C is described in ClinVar as [Benign]. Clinvar id is 785303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1857/152228) while in subpopulation AFR AF = 0.0425 (1766/41540). AF 95% confidence interval is 0.0409. There are 55 homozygotes in GnomAd4. There are 905 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 55 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
ABCA2	NM_212533.3 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 49	NP_997698.1	Q9BZC7-4
ABCA2	XM_047422921.1 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 48	XP_047278877.1
LINC02908	NR_171031.1 link	n.448+961T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	Protein	UniProt
ABCA2	ENST00000459850.5 link	n.44A>G		non_coding_transcript_exon_variant	Exon 1 of 47	1
ABCA2	ENST00000487109.5 link	n.1A>G		non_coding_transcript_exon_variant	Exon 1 of 47	1	ENSP00000418662.1	E9PGB2
ABCA2	ENST00000614293.5 link	c.1A>G	p.Met1?	start_lost	Exon 1 of 49	5	ENSP00000481105.2	Q9BZC7-4A0A087WXK5

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1849

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0424

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.00263

AC:

546

AN:

207294

AF XY:

0.00199

show subpopulations

Gnomad AFR exome

AF:

0.0430

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000735

Gnomad OTH exome

AF:

0.000833

GnomAD4 exome

AF:

0.000966

AC:

1136

AN:

1175782

Hom.:

Cov.:

AF XY:

0.000823

AC XY:

479

AN XY:

582166

show subpopulations

African (AFR)

AF:

0.0414

AC:

956

AN:

23064

American (AMR)

AF:

0.00164

AC:

AN:

31074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15976

East Asian (EAS)

AF:

0.00

AC:

AN:

12192

South Asian (SAS)

AF:

0.000129

AC:

AN:

77772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31028

Middle Eastern (MID)

AF:

0.000685

AC:

AN:

4378

European-Non Finnish (NFE)

AF:

0.0000299

AC:

AN:

937876

Other (OTH)

AF:

0.00207

AC:

AN:

42422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0122

AC:

1857

AN:

152228

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

905

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0425

AC:

1766

AN:

41540

American (AMR)

AF:

0.00399

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68010

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

181

272

362

453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00379

Hom.:

Bravo

AF:

0.0137

ESP6500AA

AF:

0.0423

AC:

162

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.00375

AC:

450

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCA2-related disorder

Benign:1

Mar 27, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.1

(source)

DANN

Benign

0.46

DEOGEN2

Benign

0.20

.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.029

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-1.0

PhyloP100

-2.7

Vest4

0.062

MVP

0.15

ClinPred

0.0012

GERP RS

-4.9

PromoterAI

-0.019

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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rs142807525

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