16-2324480-T-C

Variant names:

• chr16-2324480-T-C
• rs142977595
• NM_001089.3:c.371A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001089.3(ABCA3):​c.371A>G​(p.Asn124Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00136 in 1,610,770 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: ABCA3 NM_001089.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 4.84
• Publications: 7 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2047585).
• BP6: Variant 16-2324480-T-C is Benign according to our data. Variant chr16-2324480-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504721.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000822 (125/152024) while in subpopulation AMR AF = 0.00157 (24/15260). AF 95% confidence interval is 0.00108. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA3	NM_001089.3	MANE Select	c.371A>G	p.Asn124Ser	missense	Exon 6 of 33	NP_001080.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA3	ENST00000301732.10	TSL:1 MANE Select	c.371A>G	p.Asn124Ser	missense	Exon 6 of 33	ENSP00000301732.5
	ABCA3	ENST00000382381.7	TSL:1	c.371A>G	p.Asn124Ser	missense	Exon 6 of 32	ENSP00000371818.3
	ABCA3	ENST00000567910.1	TSL:1	c.371A>G	p.Asn124Ser	missense	Exon 5 of 6	ENSP00000454397.1

Frequencies

GnomAD3 genomes AF: 0.000823 AC: 125 AN: 151906 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.00108 AC: 268 AN: 248206 AF XY: 0.00105

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00141 AC: 2062 AN: 1458746 Hom.: 4 Cov.: 31 AF XY: 0.00143 AC XY: 1035 AN XY: 725674

African (AFR) AF: 0.000269 AC: 9 AN: 33478

American (AMR) AF: 0.000984 AC: 44 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86204

European-Finnish (FIN) AF: 0.00190 AC: 96 AN: 50468

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00166 AC: 1843 AN: 1111936

Other (OTH) AF: 0.000679 AC: 41 AN: 60364

GnomAD4 genome AF: 0.000822 AC: 125 AN: 152024 Hom.: 0 Cov.: 31 AF XY: 0.000740 AC XY: 55 AN XY: 74300

African (AFR) AF: 0.000193 AC: 8 AN: 41462

American (AMR) AF: 0.00157 AC: 24 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4794

European-Finnish (FIN) AF: 0.000661 AC: 7 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00122 AC: 83 AN: 67986

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00121

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00124 AC: 151

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00148

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.43
Sift	Benign	0.28	T
Sift4G	Benign	0.72	T
Polyphen		0.20	B
Vest4		0.79
MVP		0.89
MPC		0.27
ClinPred		0.042	T
GERP RS		5.4
Varity_R		0.063
gMVP		0.37
Mutation Taster		=97/3	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: rs142977595; hg19: chr16-2374481;