NM_001089.3:c.839G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001089.3(ABCA3):c.839G>A(p.Arg280His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,613,172 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00081 ( 2 hom. )

Consequence

ABCA3
NM_001089.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:1

Conservation

PhyloP100: 7.62

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07686183).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00133 (202/152178) while in subpopulation AMR AF= 0.00281 (43/15276). AF 95% confidence interval is 0.00215. There are 0 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA3	NM_001089.3 link	c.839G>A	p.Arg280His	missense_variant	Exon 8 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.839G>A	p.Arg280His	missense_variant	Exon 8 of 33	1	NM_001089.3	ENSP00000301732.5	Q99758-1
ABCA3	ENST00000382381.7 link	c.839G>A	p.Arg280His	missense_variant	Exon 8 of 32	1		ENSP00000371818.3	H0Y3H2
ABCA3	ENST00000563623.5 link	n.1402G>A		non_coding_transcript_exon_variant	Exon 8 of 20	1

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

202

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.0396

Gnomad AMR

AF:

0.00282

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000814

AC:

204

AN:

250544

Hom.:

AF XY:

0.000879

AC XY:

119

AN XY:

135448

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00182

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000814

AC:

1189

AN:

1460994

Hom.:

Cov.:

AF XY:

0.000816

AC XY:

593

AN XY:

726762

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00206

Gnomad4 NFE exome

AF:

0.000904

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.00133

AC:

202

AN:

152178

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74406

show subpopulations

Gnomad4 AFR

AF:

0.000530

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00130

Hom.:

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000455

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.000997

AC:

121

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency

Uncertain:3

May 10, 2021

Genetics and Molecular Pathology, SA Pathology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 27, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Pathogenic:1Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27516224, 23166334, 20656946, 36863776, 36808083, 36404394, 25712598, 24871971, 24115460, 37780198, 33708521) -

not specified

Uncertain:1

Dec 09, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg280His variant in ABCA3 has been reported in 1 individual with adult id iopathic interstitial pneumonia (Van Moorsel, 2010). It has been identified in 0 .15% (100/66624) of European chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs143008553). Computational prediction tools and conservation analysis suggest that this variant may impact the protei n, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg280His variant is uncertain. -

Bullous lung disease

Uncertain:1

Sep 19, 2023

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Heterozygous variant NM_001089:c.839G>A (p.Arg280His) in the ABCA3 gene was found on WES data in male proband (20 y.o., Caucasian) with bullous lung disease and spontaneous pneumothorax. No additional rare candidate variants (Class III-V of pathogenicity) were found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.0008265 (Date of access 13-09-2023). Clinvar contains an entry for this variant (Variation ID: 228421). This variant has been reported in 4 studies in patients with primary lung diseases with variable phenotypes, and in most cases in compound heterozygous with other pathogenic alleles (PMID: 20656946‚ 23166334‚ 27516224, 33708521). Most in silico predictors are inconclusive in the results (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: PM2. -

ABCA3-related disorder

Uncertain:1

Aug 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCA3 c.839G>A variant is predicted to result in the amino acid substitution p.Arg280His. This variant has been reported in an infant with neonatal respiratory distress without a second variant specified (Supp. Table 13, Wambach et al. 2012. PubMed ID: 23166334). It has also been reported in an individual with diffuse parenchymal lung disease with a second ABCA3 variant, though the phase of the variants was not specified (Kröner et al. 2017. PubMed ID: 27516224), and in a full term infant with severe respiratory distress syndrome in the compound heterozygous state with ABCA3 c.1897-1G>C (Wang et al. 2021. PubMed ID: 33708521). This variant is reported in 0.19% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary pulmonary alveolar proteinosis

Uncertain:1

Feb 20, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R280H variant (also known as c.839G>A), located in coding exon 5 of the ABCA3 gene, results from a G to A substitution at nucleotide position 839. The arginine at codon 280 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in the heterozygous state, in an adult patient with sporadic pulmonary fibrosis and in a newborn infant with neonatal respiratory distress syndrome (RDS) (van Moorsel CH et al. Am. J. Respir. Crit. Care Med., 2010 Dec;182:1419-25; Wambach JA et al. Pediatrics, 2012 Dec;130:e1575-82); a second alteration was not identified in either patient. In a newborn with diffuse parenchymal lung disease (DPLD) p.R280H was detected in the heterozygous state with a second alteration; phase was not confirmed, and the clinical significance and possible contribution of this variant to the patient's phenotype is unclear (Kröner C et al. Thorax, 2016 Aug; [Epub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.077

T;T

MetaSVM

Uncertain

0.53

MutationAssessor

Pathogenic

3.5

H;.

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.7

D;N

REVEL

Uncertain

0.62

Sift

Uncertain

0.016

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

1.0

D;.

Vest4

0.87

MVP

0.92

MPC

0.94

ClinPred

0.25

GERP RS

4.7

Varity_R

0.55

gMVP

0.81

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over