rs146709251

Variant names:

• chr16-2279070-G-A
• rs146709251
• NM_001089.3:c.4420C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-2279070-G-A
• chr16-2279070-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1474Q) has been classified as Uncertain significance.

• 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
• Publications: 8 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 -20 ACMG points.

• 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 Benign/Likely_benign. ClinVar VariationId is 504718.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00296 (451/152326) while in subpopulation NFE AF = 0.00409 (278/68032). AF 95% confidence interval is 0.00369. There are 1 homozygotes in GnomAd4. There are 212 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

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.4420C>T	p.Arg1474Trp	missense	Exon 29 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.4420C>T	p.Arg1474Trp	missense	Exon 29 of 33	ENSP00000301732.5	Q99758-1
	ABCA3	ENST00000382381.7	TSL:1	c.4246C>T	p.Arg1416Trp	missense	Exon 28 of 32	ENSP00000371818.3	H0Y3H2
	ABCA3	ENST00000967440.1		c.4420C>T	p.Arg1474Trp	missense	Exon 29 of 33	ENSP00000637499.1

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

GnomAD2 exomes AF: 0.00426 AC: 1068 AN: 250846 AF XY: 0.00422

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 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

African (AFR) AF: 0.000568 AC: 19 AN: 33476

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86240

European-Finnish (FIN) AF: 0.0145 AC: 761 AN: 52592

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5550

European-Non Finnish (NFE) AF: 0.00400 AC: 4453 AN: 1112006

Other (OTH) AF: 0.00353 AC: 213 AN: 60366

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

African (AFR) AF: 0.000890 AC: 37 AN: 41564

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.0122 AC: 130 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00409 AC: 278 AN: 68032

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00289 Hom.: 5

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	ABCA3-related disorder (1)
-	-	1	Hereditary pulmonary alveolar proteinosis (1)
-	-	1	Interstitial lung disease due to ABCA3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.024	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.82
Sift	Benign	0.058	T
Sift4G	Uncertain	0.027	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
Mutation Taster		=86/14	polymorphism

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: rs146709251; hg19: chr16-2329071;