rs117603931

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001089.3(ABCA3):c.863G>A(p.Arg288Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00703 in 1,612,206 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0063 ( 8 hom., cov: 31)

Exomes 𝑓: 0.0071 ( 80 hom. )

Consequence

ABCA3
NM_001089.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:7

Conservation

PhyloP100: 0.0120

Publications

30 publications found

Variant links:

Genes affected

ABCA3 (HGNC:33): (ATP binding cassette subfamily A member 3) 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. The full transporter encoded by this gene may be involved in development of resistance to xenobiotics and engulfment during programmed cell death. [provided by RefSeq, Jul 2008]

ABCA3 Gene-Disease associations (from GenCC):

interstitial lung disease due to ABCA3 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ABCA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001089.3

BP4

Computational evidence support a benign effect (MetaRNN=0.00830847).

BP6

Variant 16-2319591-C-T is Benign according to our data. Variant chr16-2319591-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227155.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00631 (961/152264) while in subpopulation NFE AF = 0.011 (745/68014). AF 95% confidence interval is 0.0103. There are 8 homozygotes in GnomAd4. There are 420 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001089.3. 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
	ABCA3	NM_001089.3	MANE Select	c.863G>A	p.Arg288Lys	missense	Exon 8 of 33	NP_001080.2	Q99758-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCA3	ENST00000301732.10	TSL:1 MANE Select	c.863G>A	p.Arg288Lys	missense	Exon 8 of 33	ENSP00000301732.5	Q99758-1
ABCA3	ENST00000382381.7	TSL:1	c.863G>A	p.Arg288Lys	missense	Exon 8 of 32	ENSP00000371818.3	H0Y3H2
ABCA3	ENST00000563623.5	TSL:1	n.1426G>A		non_coding_transcript_exon	Exon 8 of 20

Frequencies

GnomAD3 genomes

AF:

0.00632

AC:

961

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00166

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00567

AC:

1415

AN:

249708

AF XY:

0.00549

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00873

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00499

Gnomad NFE exome

AF:

0.00934

Gnomad OTH exome

AF:

0.00653

GnomAD4 exome

AF:

0.00711

AC:

10373

AN:

1459942

Hom.:

Cov.:

AF XY:

0.00711

AC XY:

5161

AN XY:

726252

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

33480

American (AMR)

AF:

0.00268

AC:

120

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0102

AC:

267

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000707

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00536

AC:

276

AN:

51534

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00831

AC:

9238

AN:

1111964

Other (OTH)

AF:

0.00613

AC:

370

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

647

1294

1942

2589

3236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

270

540

810

1080

1350

<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:

0.00631

AC:

961

AN:

152264

Hom.:

Cov.:

AF XY:

0.00564

AC XY:

420

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00166

AC:

AN:

41564

American (AMR)

AF:

0.00327

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00471

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0110

AC:

745

AN:

68014

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00899

Hom.:

Bravo

AF:

0.00556

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00826

AC:

ExAC

AF:

0.00592

AC:

719

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00834

EpiControl

AF:

0.00741

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Interstitial lung disease due to ABCA3 deficiency (3)

not specified (2)

Hereditary pulmonary alveolar proteinosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

0.62

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.17

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.71

M_CAP

Benign

0.044

MetaRNN

Benign

0.0083

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-0.050

PhyloP100

0.012

PrimateAI

Benign

0.28

PROVEAN

Benign

0.67

REVEL

Uncertain

0.47

Sift

Benign

1.0

Sift4G

Benign

0.98

Polyphen

0.0

Vest4

0.26

MVP

0.52

MPC

0.23

ClinPred

0.00055

GERP RS

-5.4

Varity_R

0.033

gMVP

0.59

Mutation Taster

=97/3

polymorphism

(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

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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