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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001089.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA3	NM_001089.3	MANE Select	c.1755C>G	p.Pro585Pro	synonymous	Exon 15 of 33	NP_001080.2	Q99758-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA3	ENST00000301732.10	TSL:1 MANE Select	c.1755C>G	p.Pro585Pro	synonymous	Exon 15 of 33	ENSP00000301732.5	Q99758-1
	ABCA3	ENST00000382381.7	TSL:1	c.1581C>G	p.Pro527Pro	synonymous	Exon 14 of 32	ENSP00000371818.3	H0Y3H2
	ABCA3	ENST00000563623.5	TSL:1	n.2318C>G		non_coding_transcript_exon	Exon 15 of 20

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary pulmonary alveolar proteinosis (1)
-	-	1	Interstitial lung disease due to ABCA3 deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;