rs201299260

Variant names:

• chr16-2319616-G-A
• rs201299260
• NM_001089.3:c.838C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2319616-G-A
• chr16-2319616-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 PP3_Moderate PP5

The NM_001089.3(ABCA3):​c.838C>T​(p.Arg280Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,613,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001167276: A functional study has demonstrated that this variant affects normal ABCA3 protein trafficking and folding." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R280H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: ABCA3 NM_001089.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4
• Conservation: PhyloP100: 9.62
• Publications: 14 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001167276: A functional study has demonstrated that this variant affects normal ABCA3 protein trafficking and folding.; SCV002817178: Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 21214890).; SCV002679768: Functional studies showed this mutation can lead to partial retention of the ABCA3 protein in the endoplasmic reticulum (ER) and induce apoptosis of lung epithelial cells (Weichert N et al. Respir. Res. 2011; 12:4).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 16-2319616-G-A is Pathogenic according to our data. Variant chr16-2319616-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 318566.

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.838C>T	p.Arg280Cys	missense	Exon 8 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.838C>T	p.Arg280Cys	missense	Exon 8 of 33	ENSP00000301732.5	Q99758-1
	ABCA3	ENST00000382381.7	TSL:1	c.838C>T	p.Arg280Cys	missense	Exon 8 of 32	ENSP00000371818.3	H0Y3H2
	ABCA3	ENST00000563623.5	TSL:1	n.1401C>T		non_coding_transcript_exon	Exon 8 of 20

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152120 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000172 AC: 43 AN: 250570 AF XY: 0.000192

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 338 AN: 1461024 Hom.: 0 Cov.: 35 AF XY: 0.000226 AC XY: 164 AN XY: 726748

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000281 AC: 313 AN: 1112002

Other (OTH) AF: 0.000199 AC: 12 AN: 60392

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152120 Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 19 AN XY: 74314

African (AFR) AF: 0.0000724 AC: 3 AN: 41426

American (AMR) AF: 0.000983 AC: 15 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000191 Hom.: 1

Bravo AF: 0.000212

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Interstitial lung disease due to ABCA3 deficiency (3)
1	1	-	not provided (2)
-	2	-	not specified (2)
1	-	-	Hereditary pulmonary alveolar proteinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.6
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.96
MPC		0.99
ClinPred		0.90	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.86
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs201299260; hg19: chr16-2369617;