rs148671332

Positions:

• chr16-2297467-G-A

Variant summary

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

The NM_001089.3(ABCA3):​c.2125C>T​(p.Arg709Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00221 in 1,613,790 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R709Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (7 hom.)
• Consequence: ABCA3 NM_001089.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 4.98

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061494887).
• BP6: Variant 16-2297467-G-A is Benign according to our data. Variant chr16-2297467-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162674.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA3	NM_001089.3	c.2125C>T	p.Arg709Trp	missense_variant	17/33	ENST00000301732.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA3	ENST00000301732.10	c.2125C>T	p.Arg709Trp	missense_variant	17/33	1	NM_001089.3	P1
ABCA3	ENST00000382381.7	c.1951C>T	p.Arg651Trp	missense_variant	16/32	1
ABCA3	ENST00000563623.5	n.2688C>T		non_coding_transcript_exon_variant	17/20	1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 247 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00130 AC: 327 AN: 251336 Hom.: 0 AF XY: 0.00119 AC XY: 162 AN XY: 135878

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00227 AC: 3321 AN: 1461530 Hom.: 7 Cov.: 32 AF XY: 0.00217 AC XY: 1581 AN XY: 727070

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000414

Gnomad4 NFE exome AF: 0.00270

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74448

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00257

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00180 Hom.: 0

Bravo AF: 0.00158

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00131 AC: 159

EpiCase AF: 0.00305

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 04, 2021	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2022	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: 22068586, 27516224, 33224783, 32238781, 34638622) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 21, 2016

Variant classified as Uncertain Significance - Favor Benign. The p.Arg709Trp var iant in ABCA3 has been reported in the heterozygous state in 1 child with neonat al respiratory distress (NRD)(Flamein 2012). This variant has also been identifi ed by our laboratory in 1 neonate with pulmonary hypertension, pulmonary valve d ysplasia, left aortic arch with aberrant right subclavian artery, cardiomyopathy (RV dilation, mild LVH), and hypotonia. It has been identified in 0.2% (24/1036 4) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs148671332). Computational prediction tools and cons ervation analysis suggest that this variant may not impact the protein, though t his information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Arg709Trp variant is uncertain, its fre quency suggests that it is more likely to be benign. -

ABCA3-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2023

The ABCA3 c.2125C>T variant is predicted to result in the amino acid substitution p.Arg709Trp. This variant has been reported in individuals with ABCA3-related disease (Flamein et al. 2012. PubMed ID: 22068586; Kröner et al. 2016. PubMed ID: 27516224; Sallmon et al. 2020. PubMed ID: 33224783). However, in one individual a second variant was not identified (Flamein et al. 2012. PubMed ID: 22068586). This variant is reported in 0.21% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2347468-G-A). 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

Oct 14, 2019

The p.R709W variant (also known as c.2125C>T), located in coding exon 14 of the ABCA3 gene, results from a C to T substitution at nucleotide position 2125. The arginine at codon 709 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was detected in an individual with interstitial lung disease; a second ABCA3 alteration was not detected (Flamein F et al. Hum. Mol. Genet., 2012 Feb;21:765-75). In addition, this variant was detected in a adult individual with dyspnea withe exercise and pulmonary alveolar proteinosis; a second ABCA3 alteration was detected, but the phase is unknown (Kröner C et al. Thorax, 2017 Mar;72:213-220). This amino acid position is poorly 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 variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.061	T;T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	0.64	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.72	P;.
Vest4		0.28
MVP		0.96
MPC		0.40
ClinPred		0.060	T
GERP RS		6.2
Varity_R		0.21
gMVP		0.72

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: rs148671332; hg19: chr16-2347468; COSMIC: COSV57060166;