rs142977595

Positions:

• chr16-2324480-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS2

The NM_001089.3(ABCA3):​c.371A>G​(p.Asn124Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00136 in 1,610,770 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.00082 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: ABCA3 NM_001089.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 4.84

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 -5 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity ABCA3_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.2047585).
• BP6: Variant 16-2324480-T-C is Benign according to our data. Variant chr16-2324480-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504721.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA3	NM_001089.3	c.371A>G	p.Asn124Ser	missense_variant	6/33	ENST00000301732.10	NP_001080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA3	ENST00000301732.10	c.371A>G	p.Asn124Ser	missense_variant	6/33	1	NM_001089.3	ENSP00000301732	P1
ABCA3	ENST00000382381.7	c.371A>G	p.Asn124Ser	missense_variant	6/32	1		ENSP00000371818
ABCA3	ENST00000567910.1	c.371A>G	p.Asn124Ser	missense_variant	5/6	1		ENSP00000454397
ABCA3	ENST00000563623.5	n.934A>G		non_coding_transcript_exon_variant	6/20	1

Frequencies

GnomAD3 genomes AF: 0.000823 AC: 125 AN: 151906 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00108 AC: 268 AN: 248206 Hom.: 1 AF XY: 0.00105 AC XY: 142 AN XY: 134600

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00141 AC: 2062 AN: 1458746 Hom.: 4 Cov.: 31 AF XY: 0.00143 AC XY: 1035 AN XY: 725674

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00190

Gnomad4 NFE exome AF: 0.00166

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000822 AC: 125 AN: 152024 Hom.: 0 Cov.: 31 AF XY: 0.000740 AC XY: 55 AN XY: 74300

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.00121

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00124 AC: 151

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency Uncertain:1

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). 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. -

Hereditary pulmonary alveolar proteinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2018

The p.N124S variant (also known as c.371A>G), located in coding exon 3 of the ABCA3 gene, results from an A to G substitution at nucleotide position 371. The asparagine at codon 124 is replaced by serine, an amino acid with highly similar properties. A study of the N-linked glycosylation site at residue 124 found that single mutations at the glycosylation site fail to disrupt the trafficking pattern of ABCA3 to cytosolic lysosomal-related organelles or alter their function as lipid transporters (Beers MF et al. Am. J. Physiol. Lung Cell Mol. Physiol., 2013 Dec;305:L970-80). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 22, 2019

The p.Asn124Ser variant in ABCA3 is classified as likely benign because it has has been identified in 0.16% (209/128312) of European and 0.13% (32/23120) of Finnish chromosomes including 1 homozygote by gnomAD (http://gnomad.broadinstitute.org), and because computational prediction tools and conservation analysis suggest that the variant may not impact the protein. ACMG/AMP criteria applied: BS1_Supporting, BP4. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.6	L;.;L
MutationTaster	Benign	0.72	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.20	B;.;.
Vest4		0.79
MVP		0.89
MPC		0.27
ClinPred		0.042	T
GERP RS		5.4
Varity_R		0.063
gMVP		0.37

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: rs142977595; hg19: chr16-2374481;