rs117603931

Positions:

• chr16-2319591-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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. 15/21 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 0.0120

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• 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 id is 227155.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3, Benign=1}.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA3	NM_001089.3	c.863G>A	p.Arg288Lys	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.863G>A	p.Arg288Lys	missense_variant	8/33	1	NM_001089.3	ENSP00000301732.5
ABCA3	ENST00000382381.7	c.863G>A	p.Arg288Lys	missense_variant	8/32	1		ENSP00000371818.3
ABCA3	ENST00000563623.5	n.1426G>A		non_coding_transcript_exon_variant	8/20	1

Frequencies

GnomAD3 genomes AF: 0.00632 AC: 961 AN: 152150 Hom.: 8 Cov.: 31

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

GnomAD3 exomes AF: 0.00567 AC: 1415 AN: 249708 Hom.: 9 AF XY: 0.00549 AC XY: 741 AN XY: 135006

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 SAS exome AF: 0.000653

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.: 80 Cov.: 35 AF XY: 0.00711 AC XY: 5161 AN XY: 726252

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.00268

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.00536

Gnomad4 NFE exome AF: 0.00831

Gnomad4 OTH exome AF: 0.00613

GnomAD4 genome AF: 0.00631 AC: 961 AN: 152264 Hom.: 8 Cov.: 31 AF XY: 0.00564 AC XY: 420 AN XY: 74450

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00471

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00948 Hom.: 15

Bravo AF: 0.00556

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00592 AC: 719

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00834

EpiControl AF: 0.00741

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2020	This variant is associated with the following publications: (PMID: 30413314, 24871971, 29255193, 26928390, 23166334, 27374344, 27516224, 16728712, 20981092, 22995991, 22304854, 25073622) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	ABCA3: BP4, BS2 -

Interstitial lung disease due to ABCA3 deficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jan 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 24, 2019	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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 15, 2015

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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2017

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	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	0.62
DANN	Benign	0.59
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.0083	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.050	N;.
PrimateAI	Benign	0.28	T
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	T
GERP RS		-5.4
Varity_R		0.033
gMVP		0.59

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: rs117603931; hg19: chr16-2369592; COSMIC: COSV57050489; COSMIC: COSV57050489;