16-2300114-G-T

Variant names:

• chr16-2300114-G-T
• rs141621969
• NM_001089.3:c.1502C>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001089.3(ABCA3):​c.1502C>A​(p.Ala501Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,613,474 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.0030 (5 hom., cov: 30)
  • Exomes 𝑓: 0.0026 (40 hom.)
• Consequence: ABCA3 NM_001089.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:7
• Conservation: PhyloP100: 2.88

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064069927).
• BP6: Variant 16-2300114-G-T is Benign according to our data. Variant chr16-2300114-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178700.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=3, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00295 (448/151680) while in subpopulation AMR AF= 0.00607 (92/15166). AF 95% confidence interval is 0.00506. There are 5 homozygotes in gnomad4. There are 228 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA3	NM_001089.3	c.1502C>A	p.Ala501Glu	missense_variant	Exon 13 of 33	ENST00000301732.10	NP_001080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA3	ENST00000301732.10	c.1502C>A	p.Ala501Glu	missense_variant	Exon 13 of 33	1	NM_001089.3	ENSP00000301732.5
ABCA3	ENST00000382381.7	c.1328C>A	p.Ala443Glu	missense_variant	Exon 12 of 32	1		ENSP00000371818.3
ABCA3	ENST00000563623.5	n.2065C>A		non_coding_transcript_exon_variant	Exon 13 of 20	1

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 448 AN: 151562 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.000267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00607

Gnomad ASJ AF: 0.0445

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00460

Gnomad FIN AF: 0.000379

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.00721

GnomAD3 exomes AF: 0.00410 AC: 1031 AN: 251412 Hom.: 16 AF XY: 0.00434 AC XY: 590 AN XY: 135876

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.0430

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00438

Gnomad FIN exome AF: 0.000694

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.00264 AC: 3855 AN: 1461794 Hom.: 40 Cov.: 32 AF XY: 0.00283 AC XY: 2061 AN XY: 727194

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.0408

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00412

Gnomad4 FIN exome AF: 0.000731

Gnomad4 NFE exome AF: 0.00149

Gnomad4 OTH exome AF: 0.00608

GnomAD4 genome AF: 0.00295 AC: 448 AN: 151680 Hom.: 5 Cov.: 30 AF XY: 0.00308 AC XY: 228 AN XY: 74110

Gnomad4 AFR AF: 0.000266

Gnomad4 AMR AF: 0.00607

Gnomad4 ASJ AF: 0.0445

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00460

Gnomad4 FIN AF: 0.000379

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.00714

Alfa AF: 0.00420 Hom.: 10

Bravo AF: 0.00321

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00385 AC: 467

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00427

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency Uncertain:1 Benign:3

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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). 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. -

Feb 11, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2019

Genetics and Molecular Pathology, SA Pathology

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

Dec 11, 2015

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 08, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Ala501Glu variant of ABCA3 has been previously identified in one individual with severe pulmonary hypertension and histological/ultrastructural analyses con sistent with ABCA3 deficiency (Danhaive 2008). This variant is present in 0.46% (40/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs141621969). Alanine (Ala) at positi on 501 is poorly conserved in evolution and other computational analyses (bioche mical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that the ch ange to glutamic acid (Glu) may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant is less likely disease causing but additional information is needed to fully assess its clinical significance. -

not provided Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA3: BP4, BS2 -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pulmonary alveolar proteinosis Benign:1

Apr 18, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.095
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	4.1
DANN	Benign	0.30
DEOGEN2	Benign	0.074	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.36	T;T
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	-0.76	N;.
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.33	N;N
REVEL	Uncertain	0.49
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.14
MVP		0.60
MPC		0.26
ClinPred		0.0052	T
GERP RS		0.86
Varity_R		0.028
gMVP		0.79

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: rs141621969; hg19: chr16-2350115;