16-2300114-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000301732.10(ABCA3):c.1502C>A(p.Ala501Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,613,474 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.0030 ( 5 hom., cov: 30)

Exomes 𝑓: 0.0026 ( 40 hom. )

Consequence

ABCA3
ENST00000301732.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 2.88

Publications

10 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: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0064069927).

BP6

Variant 16-2300114-G-T is Benign according to our data. Variant chr16-2300114-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178700.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00295 (448/151680) while in subpopulation AMR AF = 0.00607 (92/15166). AF 95% confidence interval is 0.00506. There are 5 homozygotes in GnomAd4. There are 228 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000301732.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA3	NM_001089.3	MANE Select	c.1502C>A	p.Ala501Glu	missense	Exon 13 of 33	NP_001080.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCA3	ENST00000301732.10	TSL:1 MANE Select	c.1502C>A	p.Ala501Glu	missense	Exon 13 of 33	ENSP00000301732.5
ABCA3	ENST00000382381.7	TSL:1	c.1328C>A	p.Ala443Glu	missense	Exon 12 of 32	ENSP00000371818.3
ABCA3	ENST00000563623.5	TSL:1	n.2065C>A		non_coding_transcript_exon	Exon 13 of 20

Frequencies

GnomAD3 genomes

AF:

0.00296

AC:

448

AN:

151562

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000267

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00607

Gnomad ASJ

AF:

0.0445

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00460

Gnomad FIN

AF:

0.000379

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.00721

GnomAD2 exomes

AF:

0.00410

AC:

1031

AN:

251412

AF XY:

0.00434

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00304

Gnomad ASJ exome

AF:

0.0430

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000694

Gnomad NFE exome

AF:

0.00261

Gnomad OTH exome

AF:

0.00750

GnomAD4 exome

AF:

0.00264

AC:

3855

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

2061

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.000866

AC:

AN:

33478

American (AMR)

AF:

0.00340

AC:

152

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0408

AC:

1067

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00412

AC:

355

AN:

86258

European-Finnish (FIN)

AF:

0.000731

AC:

AN:

53330

Middle Eastern (MID)

AF:

0.0321

AC:

185

AN:

5768

European-Non Finnish (NFE)

AF:

0.00149

AC:

1661

AN:

1112008

Other (OTH)

AF:

0.00608

AC:

367

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

260

520

780

1040

1300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<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:

0.00295

AC:

448

AN:

151680

Hom.:

Cov.:

AF XY:

0.00308

AC XY:

228

AN XY:

74110

show subpopulations

African (AFR)

AF:

0.000266

AC:

AN:

41314

American (AMR)

AF:

0.00607

AC:

AN:

15166

Ashkenazi Jewish (ASJ)

AF:

0.0445

AC:

154

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00460

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.000379

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00215

AC:

146

AN:

67906

Other (OTH)

AF:

0.00714

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00336

Hom.:

Bravo

AF:

0.00321

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00385

AC:

467

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.00447

EpiControl

AF:

0.00427

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Interstitial lung disease due to ABCA3 deficiency (5)

not provided (2)

not specified (2)

Hereditary pulmonary alveolar proteinosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

4.1

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.074

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.36

MetaRNN

Benign

0.0064

MetaSVM

Benign

-0.55

MutationAssessor

Benign

-0.76

PhyloP100

2.9

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.33

REVEL

Uncertain

0.49

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.14

MVP

0.60

MPC

0.26

ClinPred

0.0052

GERP RS

0.86

Varity_R

0.028

gMVP

0.79

Mutation Taster

=99/1

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over