rs142977595

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM1BP4_ModerateBP6BS1BS2

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

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PM1

In a mutagenesis_site Loss of N-glycosylation. Reduces protein expression by 50%. Affects anterograde trafficking; when associated with Q-140. Reduces protein expression by 85%; when associated with Q-140. Does not affect lamellar body membrane location. (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}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000822 (125/152024) while in subpopulation AMR AF= 0.00157 (24/15260). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

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.371A>G	p.Asn124Ser	missense_variant	Exon 6 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.371A>G	p.Asn124Ser	missense_variant	Exon 6 of 33	1	NM_001089.3	ENSP00000301732.5	Q99758-1
ABCA3	ENST00000382381.7 link	c.371A>G	p.Asn124Ser	missense_variant	Exon 6 of 32	1		ENSP00000371818.3	H0Y3H2
ABCA3	ENST00000567910.1 link	c.371A>G	p.Asn124Ser	missense_variant	Exon 5 of 6	1		ENSP00000454397.1	Q99758-2
ABCA3	ENST00000563623.5 link	n.934A>G		non_coding_transcript_exon_variant	Exon 6 of 20	1

Frequencies

GnomAD3 genomes

AF:

0.000823

AC:

125

AN:

151906

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00105

AC XY:

142

AN XY:

134600

show subpopulations

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.:

Cov.:

AF XY:

0.00143

AC XY:

1035

AN XY:

725674

show subpopulations

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.:

Cov.:

AF XY:

0.000740

AC XY:

AN XY:

74300

show subpopulations

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.:

Bravo

AF:

0.00121

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00124

AC:

151

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency

Uncertain:1

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. -

Hereditary pulmonary alveolar proteinosis

Uncertain:1

Feb 26, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 22, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.21

T;.;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.6

L;.;L

PrimateAI

Benign

0.41

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

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

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