rs45592239

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001089.3(ABCA3):c.2296C>T(p.Pro766Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,614,026 control chromosomes in the GnomAD database, including 5 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). Synonymous variant affecting the same amino acid position (i.e. P766P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 4 hom. )

Consequence

ABCA3
NM_001089.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 3.56

Publications

11 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=0.010553002).

BP6

Variant 16-2295708-G-A is Benign according to our data. Variant chr16-2295708-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178696.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00169 (258/152358) while in subpopulation NFE AF = 0.00329 (224/68030). AF 95% confidence interval is 0.00294. There are 1 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA3	NM_001089.3 link	c.2296C>T	p.Pro766Ser	missense_variant	Exon 18 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.2296C>T	p.Pro766Ser	missense_variant	Exon 18 of 33	1	NM_001089.3	ENSP00000301732.5	Q99758-1
ABCA3	ENST00000382381.7 link	c.2122C>T	p.Pro708Ser	missense_variant	Exon 17 of 32	1		ENSP00000371818.3	H0Y3H2
ABCA3	ENST00000563623.5 link	n.2859C>T		non_coding_transcript_exon_variant	Exon 18 of 20	1

Frequencies

GnomAD3 genomes

AF:

0.00167

AC:

255

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00329

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00171

AC:

429

AN:

251166

AF XY:

0.00179

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00338

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00218

AC:

3193

AN:

1461668

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

1515

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000951

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000320

AC:

AN:

53196

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00266

AC:

2959

AN:

1112012

Other (OTH)

AF:

0.00192

AC:

116

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

230

459

689

918

1148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.00169

AC:

258

AN:

152358

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

104

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41588

American (AMR)

AF:

0.000196

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00329

AC:

224

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00250

Hom.:

Bravo

AF:

0.00152

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00192

AC:

233

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00240

EpiControl

AF:

0.00261

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency

Uncertain:2

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Oct 28, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This ABCA3 variant has been reported in the heterozygous state and as part of a complex allele with p.Leu960Phe. This patient does not carry the latter variant and the clinical significance of p.Pro766Ser alone is unclear. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. One submitter classified it as a variant of uncertain clinical significance and one as likely benign. Of three bioinformatics tools queried, two predict that the substitution would be damaging, while one predicts that it would be tolerated. The proline residue at this position is highly evolutionarily conserved across most higher order species. Due to insufficient evidence, we consider the clinical significance of c.2296C>T to be uncertain at this time. -

not specified

Uncertain:1Benign:1

Nov 05, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Pro766Ser var iant in ABCA3 has been reported in at least 10 individuals with various pulmonar y phenotypes (Baekvad-Hansen 2012). In addition, this variant has been identifie d in 0.26% (22/8600) of European American chromosomes by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs45592239). Computational prediction tools and conservation analysis suggest that the p.Pro766Ser variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In fact, 2 fish species (southern platyfish and spotted gar) carry a serine (Ser) at this position, suggesting that this change may be tolerated. In summary, while the clinical significance of the p.Pro766Ser varian t is uncertain, its frequency and the presence of the variant amino acid in othe r species suggests that it is more likely to be benign. -

Oct 14, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Oct 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 23, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in the heterozygous state in four individuals with variable pulmnoary phenotypes including asthma, COPD, and interstitial lung disease, and in 121 patients from a general population health study (Copenhagen City Heart study) without a significant pulmonary phenotype, including one individual who was compound heterozygous for P766S and another missense variant (PMID: 22866751); 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: 35170262, 36808083, 24871971, 23625987, 22866751, 16641205, 34638622) -

Hereditary pulmonary alveolar proteinosis

Uncertain:1

Jan 25, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P766S variant (also known as c.2296C>T), located in coding exon 15 of the ABCA3 gene, results from a C to T substitution at nucleotide position 2296. The proline at codon 766 is replaced by serine, an amino acid with similar properties. This variant was identified in cis with p.L960F and in trans with a frameshift alteration in an infant with progressive lung disease and a histopathologic diagnosis of pulmonary alveolar proteinosis (Garmany TH et al. Pediatr. Res., 2006 Jun;59:801-5). In another study, the complex allele, p.[P766S; L960F], was identified in four individuals with severe pulmonary symptoms and a third ABCA3 alteration in trans (Wambach JA et al. Am. J. Respir. Crit. Care Med., 2014 Jun;189:1538-43). The p.P766S variant was identified in conjunction with two additional ABCA3 alterations in an individual with interstitial lung disease and chronic interstitial pneumonitis diagnosed at one year of age and a history of respiratory distress syndrome at birth; however, the phase of the alterations was not provided (Turcu S et al. Arch. Dis. Child., 2013 Jul;98:490-5).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.

Eigen

Benign

-0.066

Eigen_PC

Benign

0.091

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.1

L;.

PhyloP100

3.6

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Benign

0.11

Sift

Benign

0.041

D;D

Sift4G

Benign

0.19

T;T

Polyphen

0.22

B;.

Vest4

0.30

MVP

0.71

MPC

0.27

ClinPred

0.044

GERP RS

4.7

Varity_R

0.25

gMVP

0.76

Mutation Taster

=88/12

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