rs146709251

chr16-2279070-G-Achr16-2279070-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_001089.3(ABCA3):c.4420C>T(p.Arg1474Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,613,114 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1474R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (15 hom.)
• Consequence: ABCA3 NM_001089.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.53

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 -14 ACMG points.

• PM1: In a domain ABC transporter 2 (size 233) in uniprot entity ABCA3_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_001089.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.02362299).
• BP6: Variant 16-2279070-G-A is Benign according to our data. Variant chr16-2279070-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 504718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2279070-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA3	NM_001089.3	c.4420C>T	p.Arg1474Trp	missense_variant	29/33	ENST00000301732.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA3	ENST00000301732.10	c.4420C>T	p.Arg1474Trp	missense_variant	29/33	1	NM_001089.3	P1
ABCA3	ENST00000382381.7	c.4246C>T	p.Arg1416Trp	missense_variant	28/32	1
ABCA3	ENST00000566200.1	n.941C>T		non_coding_transcript_exon_variant	4/5	3

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 451 AN: 152208 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00409

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00426 AC: 1068 AN: 250846 Hom.: 5 AF XY: 0.00422 AC XY: 573 AN XY: 135798

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.0147

Gnomad NFE exome AF: 0.00610

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00377 AC: 5506 AN: 1460788 Hom.: 15 Cov.: 32 AF XY: 0.00367 AC XY: 2666 AN XY: 726730

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000603

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.00400

Gnomad4 OTH exome AF: 0.00353

GnomAD4 genome AF: 0.00296 AC: 451 AN: 152326 Hom.: 1 Cov.: 33 AF XY: 0.00285 AC XY: 212 AN XY: 74472

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.00409

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00327 Hom.: 2

Bravo AF: 0.00203

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00523 AC: 635

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2020	This variant is associated with the following publications: (PMID: 22866751, 25553246, 28724397, 23166334, 27374344) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Arg1474Trp in exon 29 of ABCA3: This variant is not expected to have clinical si gnificance because it has been identified in 3.8% (7/186) of Finnish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.go v/projects/SNP; dbSNP rs146709251). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 19, 2017	- -

Interstitial lung disease due to ABCA3 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 14, 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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

ABCA3-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary pulmonary alveolar proteinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 09, 2016

This alteration is classified as 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	0.10
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.024	T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Pathogenic	0.82
Sift	Benign	0.058	T;T
Sift4G	Uncertain	0.027	D;D
Polyphen		0.69	P;.
Vest4		0.60
MVP		0.98
MPC		0.35
ClinPred		0.063	T
GERP RS		3.3
Varity_R		0.20
gMVP		0.93

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: rs146709251; hg19: chr16-2329071;