16-2319591-C-T

Variant names:

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:6

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: 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 -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, 5 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA3	NM_001089.3 link	c.863G>A	p.Arg288Lys	missense_variant	Exon 8 of 33	ENST00000301732.10	NP_001080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ABCA3	ENST00000301732.10 link	c.863G>A	p.Arg288Lys	missense_variant	Exon 8 of 33	1	NM_001089.3	ENSP00000301732.5
ABCA3	ENST00000382381.7 link	c.863G>A	p.Arg288Lys	missense_variant	Exon 8 of 32	1		ENSP00000371818.3
ABCA3	ENST00000563623.5 link	n.1426G>A		non_coding_transcript_exon_variant	Exon 8 of 20	1

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCA3: BP4, BS2 -

Feb 26, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30413314, 24871971, 29255193, 26928390, 23166334, 27374344, 27516224, 16728712, 20981092, 22995991, 22304854, 25073622) -

Feb 27, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Interstitial lung disease due to ABCA3 deficiency

Uncertain:3

Sep 24, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This ABCA3 variant (rs117603931) reaches polymorphic frequency (greater or equal than 1%) within the European (non-Finnish) subpopulation in large population datasets (gnomAD: 1324/129014 total alleles; 1.03%; 11 homozygotes). Two submitters in ClinVar classify this variant as likely benign. This variant was previously reported as a potential disease-associated variant, however, in both cases it was located on the same chromosome (in cis) as a second, likely more deleterious ABCA3 variant. Two bioinformatic tools queried predict that this substitution would be tolerated, and the arginine residue at this position is not evolutionarily conserved across the species assessed. Multiple studies suggest that this variant may impact the function of ABCA3. Per our review and consultation with a clinical expert, this variant may contribute to an increased risk of neonatal respiratory distress in combination with other genetic and environmental factors. The clinical significance of c.863G>A is uncertain at this time. -

Jan 05, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not specified

Benign:1

Jan 15, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg288Lys in exon 8 of ABCA3: This variant is not expected to have clinical si gnificance because it has been identified in 0.95% (642/67532) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs117603931). In addition, multiple mammals (>10) carry a lysine (Lys) a t this position, supporting that this change is tolerated. While this variant ha s been reported in 2 individuals with pulmonary disease (Brasch 2006, Copertino 2012), its frequency in the general population and presence of the variant amino acid in multiple mammals supports that this variant is not likely a primary cau se of disease. -

Hereditary pulmonary alveolar proteinosis

Benign:1

May 02, 2017

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

0.062

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

0.62

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.17

T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.0083

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

-0.050

N;.

PhyloP100

0.012

PrimateAI

Benign

0.28

PROVEAN

Benign

0.67

N;N

REVEL

Uncertain

0.47

Sift

Benign

1.0

T;T

Sift4G

Benign

0.98

T;T

Polyphen

0.0

B;.

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over