chr16-2319615-C-T

Position:

• chr16-2319615-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:1
• Conservation: PhyloP100: 7.62

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07686183).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA3	NM_001089.3	c.839G>A	p.Arg280His	missense_variant	8/33	ENST00000301732.10	NP_001080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA3	ENST00000301732.10	c.839G>A	p.Arg280His	missense_variant	8/33	1	NM_001089.3	ENSP00000301732	P1
ABCA3	ENST00000382381.7	c.839G>A	p.Arg280His	missense_variant	8/32	1		ENSP00000371818
ABCA3	ENST00000563623.5	n.1402G>A		non_coding_transcript_exon_variant	8/20	1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 202 AN: 152060 Hom.: 0 Cov.: 31

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.: 1 AF XY: 0.000879 AC XY: 119 AN XY: 135448

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.: 2 Cov.: 35 AF XY: 0.000816 AC XY: 593 AN XY: 726762

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.: 0 Cov.: 31 AF XY: 0.00124 AC XY: 92 AN XY: 74406

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.: 0

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000997 AC: 121

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 27, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 10, 2021	- -

not provided Pathogenic:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2024	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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 09, 2015

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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 19, 2023

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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 20, 2019

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	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.077	T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Pathogenic	3.5	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
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	T
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

Other links and lift over

dbSNP: rs143008553; hg19: chr16-2369616; COSMIC: COSV57058585; COSMIC: COSV57058585;