chr16-2326201-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001089.3(ABCA3):c.128G>A(p.Arg43His) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ABCA3
NM_001089.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.67

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 16-2326201-C-T is Pathogenic according to our data. Variant chr16-2326201-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA3	NM_001089.3 link	c.128G>A	p.Arg43His	missense_variant	Exon 5 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.128G>A	p.Arg43His	missense_variant	Exon 5 of 33	1	NM_001089.3	ENSP00000301732.5	Q99758-1
ABCA3	ENST00000382381.7 link	c.128G>A	p.Arg43His	missense_variant	Exon 5 of 32	1		ENSP00000371818.3	H0Y3H2
ABCA3	ENST00000567910.1 link	c.128G>A	p.Arg43His	missense_variant	Exon 4 of 6	1		ENSP00000454397.1	Q99758-2
ABCA3	ENST00000563623.5 link	n.691G>A		non_coding_transcript_exon_variant	Exon 5 of 20	1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251334

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 06, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 15, 2024	- -

Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 26, 2015

The p.Arg43His variant in ABCA3 has been previously reported in 1 homozygous inf ant with interstitial lung disease (ILD) and in 3 compound heterozygous infants/ children with ILD (Doan 2008, Agrawal 2012, Wambach 2014). In addition, two othe r variants at this codon (p.Arg43Leu and p.Arg43Cys) have each been reported in 2 compound heterozygous children with ILD and one of these variants (p.Arg43Cys) segregated with disease in an affected relative, suggesting that changes to thi s residue are not tolerated (Brasch 2006, Garmany 2006, Agrawal 2012, Wambach 20 14). The p.Arg43His variant has been identified in 1/66674 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Alth ough this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational predic tion tools and conservation analysis do not provide strong support for or agains t an impact the protein. In summary, this variant meets our criteria to be class ified as pathogenic for ILD in an autosomal recessive manner(http://www.partners .org/personalizedmedicine/LMM). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 43 of the ABCA3 protein (p.Arg43His). This variant is present in population databases (rs754714105, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive childhood interstitial lung disease (PMID: 18024538, 24871971). ClinVar contains an entry for this variant (Variation ID: 228321). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA3 protein function. This variant disrupts the p.Arg43 amino acid residue in ABCA3. Other variant(s) that disrupt this residue have been observed in individuals with ABCA3-related conditions (PMID: 22337229, 24871971), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Hereditary pulmonary alveolar proteinosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2022

The p.R43H pathogenic mutation (also known as c.128G>A), located in coding exon 2 of the ABCA3 gene, results from a G to A substitution at nucleotide position 128. The arginine at codon 43 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in the homozygous state or in conjunction with other ABCA3 disease-causing variants in multiple individuals with ABCA3-related surfactant dysfunction (Doan ML et al. Thorax, 2008 Apr;63:366-73; Agrawal A et al. Pediatr Res, 2012 Jun;71:633-7; Wambach JA et al. Am J Respir Crit Care Med, 2014 Jun;189:1538-43; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;.;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;.;M

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.023

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.82

MutPred

0.89

Loss of catalytic residue at R43 (P = 0.0382);Loss of catalytic residue at R43 (P = 0.0382);Loss of catalytic residue at R43 (P = 0.0382);

MVP

0.99

MPC

0.94

ClinPred

0.98

GERP RS

5.7

Varity_R

0.33

gMVP

0.92

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