16-2300114-G-T

Variant names:

Variant summary

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

The NM_001089.3(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
NM_001089.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

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 id is 178700.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA3	NM_001089.3 link	c.1502C>A	p.Ala501Glu	missense_variant	Exon 13 of 33	ENST00000301732.10	NP_001080.2	Q99758-1Q4LE27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCA3	ENST00000301732.10 link	c.1502C>A	p.Ala501Glu	missense_variant	Exon 13 of 33	1	NM_001089.3	ENSP00000301732.5	Q99758-1
ABCA3	ENST00000382381.7 link	c.1328C>A	p.Ala443Glu	missense_variant	Exon 12 of 32	1		ENSP00000371818.3	H0Y3H2
ABCA3	ENST00000563623.5 link	n.2065C>A		non_coding_transcript_exon_variant	Exon 13 of 20	1

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

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

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency

Uncertain:1Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Aug 01, 2019

Genetics and Molecular Pathology, SA Pathology

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 11, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 22, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Nov 08, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Ala501Glu variant of ABCA3 has been previously identified in one individual with severe pulmonary hypertension and histological/ultrastructural analyses con sistent with ABCA3 deficiency (Danhaive 2008). This variant is present in 0.46% (40/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs141621969). Alanine (Ala) at positi on 501 is poorly conserved in evolution and other computational analyses (bioche mical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that the ch ange to glutamic acid (Glu) may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant is less likely disease causing but additional information is needed to fully assess its clinical significance. -

Dec 11, 2015

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCA3: BP4, BS2 -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary pulmonary alveolar proteinosis

Benign:1

Apr 18, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

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

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.36

T;T

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

-0.76

N;.

PhyloP100

2.9

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.33

N;N

REVEL

Uncertain

0.49

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

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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16-2300114-G-T

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