16-2298527-G-C

Variant names:

• chr16-2298527-G-C
• rs323043
• NM_001089.3:c.1755C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001089.3(ABCA3):​c.1755C>G​(p.Pro585Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,613,380 control chromosomes in the GnomAD database, including 26,701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P585P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1810 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24891 hom.)
• Consequence: ABCA3 NM_001089.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.27
• Publications: 29 publications found

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 Gene-Disease associations (from GenCC):

• interstitial lung disease due to ABCA3 deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-2298527-G-C is Benign according to our data. Variant chr16-2298527-G-C is described in ClinVar as Benign. ClinVar VariationId is 178697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA3	NM_001089.3	c.1755C>G	p.Pro585Pro	synonymous_variant	Exon 15 of 33	ENST00000301732.10	NP_001080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA3	ENST00000301732.10	c.1755C>G	p.Pro585Pro	synonymous_variant	Exon 15 of 33	1	NM_001089.3	ENSP00000301732.5
ABCA3	ENST00000382381.7	c.1581C>G	p.Pro527Pro	synonymous_variant	Exon 14 of 32	1		ENSP00000371818.3
ABCA3	ENST00000563623.5	n.2318C>G		non_coding_transcript_exon_variant	Exon 15 of 20	1

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21505 AN: 152068 Hom.: 1811 Cov.: 32

Gnomad AFR AF: 0.0671

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.0234

Gnomad SAS AF: 0.0759

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.142 AC: 35540 AN: 251100 AF XY: 0.143

Gnomad AFR exome AF: 0.0651

Gnomad AMR exome AF: 0.0718

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.0247

Gnomad FIN exome AF: 0.204

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.177 AC: 257989 AN: 1461194 Hom.: 24891 Cov.: 34 AF XY: 0.174 AC XY: 126584 AN XY: 726914

African (AFR) AF: 0.0669 AC: 2238 AN: 33476

American (AMR) AF: 0.0784 AC: 3506 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.195 AC: 5102 AN: 26134

East Asian (EAS) AF: 0.0265 AC: 1052 AN: 39698

South Asian (SAS) AF: 0.0778 AC: 6710 AN: 86230

European-Finnish (FIN) AF: 0.207 AC: 10963 AN: 53060

Middle Eastern (MID) AF: 0.169 AC: 951 AN: 5620

European-Non Finnish (NFE) AF: 0.196 AC: 217386 AN: 1111892

Other (OTH) AF: 0.167 AC: 10081 AN: 60368

GnomAD4 genome AF: 0.141 AC: 21509 AN: 152186 Hom.: 1810 Cov.: 32 AF XY: 0.140 AC XY: 10432 AN XY: 74418

African (AFR) AF: 0.0672 AC: 2793 AN: 41536

American (AMR) AF: 0.122 AC: 1865 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 655 AN: 3470

East Asian (EAS) AF: 0.0230 AC: 119 AN: 5168

South Asian (SAS) AF: 0.0753 AC: 363 AN: 4820

European-Finnish (FIN) AF: 0.203 AC: 2152 AN: 10600

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.191 AC: 13019 AN: 67988

Other (OTH) AF: 0.150 AC: 318 AN: 2114

Alfa AF: 0.168 Hom.: 1915

Bravo AF: 0.134

Asia WGS AF: 0.0560 AC: 195 AN: 3478

EpiCase AF: 0.191

EpiControl AF: 0.187

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 24, 2018

GeneDx

Significance: 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro585Pro in exon 15 of ABCA3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 19.8% (1702/8600) o f European American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs323043). -

Interstitial lung disease due to ABCA3 deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary pulmonary alveolar proteinosis Benign:1

Oct 14, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.43
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs323043; hg19: chr16-2348528; COSMIC: COSV57053681;