16-2317763-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 9P and 6B. PP3PP5_Very_StrongBP4BS1_SupportingBS2

The NM_001089.3(ABCA3):c.875A>T(p.Glu292Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00453 in 1,613,934 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 20 hom. )

Consequence

ABCA3
NM_001089.3 missense, splice_region

Scores

Splicing: ADA: 0.6552

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23

Conservation

PhyloP100: 7.41

Publications

73 publications found

Variant links:

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

ABCA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, dbscSNV1_RF, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when dbscSNV1_ADA, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]

PP5

Variant 16-2317763-T-A is Pathogenic according to our data. Variant chr16-2317763-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 203381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.18085593). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00298 (454/152358) while in subpopulation NFE AF = 0.00501 (341/68030). AF 95% confidence interval is 0.00457. There are 0 homozygotes in GnomAd4. There are 213 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 20 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.875A>T	p.Glu292Val	missense splice_region	Exon 9 of 33	NP_001080.2	Q99758-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCA3	ENST00000301732.10	TSL:1 MANE Select	c.875A>T	p.Glu292Val	missense splice_region	Exon 9 of 33	ENSP00000301732.5	Q99758-1
ABCA3	ENST00000382381.7	TSL:1	c.875A>T	p.Glu292Val	missense splice_region	Exon 9 of 32	ENSP00000371818.3	H0Y3H2
ABCA3	ENST00000563623.5	TSL:1	n.1438A>T		splice_region non_coding_transcript_exon	Exon 9 of 20

Frequencies

GnomAD3 genomes

AF:

0.00298

AC:

454

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00294

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00501

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00229

AC:

576

AN:

250982

AF XY:

0.00238

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00130

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000555

Gnomad NFE exome

AF:

0.00434

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.00469

AC:

6862

AN:

1461576

Hom.:

Cov.:

AF XY:

0.00457

AC XY:

3324

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

33472

American (AMR)

AF:

0.00130

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000693

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00584

AC:

6488

AN:

1111792

Other (OTH)

AF:

0.00397

AC:

240

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

388

776

1163

1551

1939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

250

500

750

1000

1250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00298

AC:

454

AN:

152358

Hom.:

Cov.:

AF XY:

0.00286

AC XY:

213

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41592

American (AMR)

AF:

0.00294

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00501

AC:

341

AN:

68030

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00430

Hom.:

Bravo

AF:

0.00309

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00453

AC:

ExAC

AF:

0.00223

AC:

271

EpiCase

AF:

0.00436

EpiControl

AF:

0.00403

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Interstitial lung disease due to ABCA3 deficiency (13)

not provided (7)

Diffuse interstitial pulmonary fibrosis;C5680383:Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies (1)

Hereditary pulmonary alveolar proteinosis (1)

Interstitial lung disease 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.18

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.7

PhyloP100

7.4

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.93

MVP

0.97

MPC

0.92

ClinPred

0.90

GERP RS

5.0

Varity_R

0.91

gMVP

0.87

Mutation Taster

=28/72

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.66

dbscSNV1_RF

Pathogenic

0.78

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over