16-2281229-C-T

Variant names:

• chr16-2281229-C-T
• rs138769732
• NM_001089.3:c.4165-8G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001089.3(ABCA3):​c.4165-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00786 in 1,613,398 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0079 (70 hom.)
• Consequence: ABCA3 NM_001089.3 splice_region, intron
• Scores: Splicing: ADA: 0.00009240
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.504

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-2281229-C-T is Benign according to our data. Variant chr16-2281229-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 504719.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 = 0.00746 (1136/152340) while in subpopulation NFE AF= 0.00928 (631/68028). AF 95% confidence interval is 0.00868. There are 10 homozygotes in gnomad4. There are 581 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA3	NM_001089.3	c.4165-8G>A		splice_region_variant, intron_variant	Intron 27 of 32	ENST00000301732.10	NP_001080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA3	ENST00000301732.10	c.4165-8G>A		splice_region_variant, intron_variant	Intron 27 of 32	1	NM_001089.3	ENSP00000301732.5
ABCA3	ENST00000382381.7	c.3991-8G>A		splice_region_variant, intron_variant	Intron 26 of 31	1		ENSP00000371818.3
ABCA3	ENST00000566200.1	n.686-8G>A		splice_region_variant, intron_variant	Intron 2 of 4	3
ABCA3	ENST00000569062.1	n.*164G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00749 AC: 1140 AN: 152222 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00178

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00426

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0211

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00927

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00824 AC: 2065 AN: 250606 Hom.: 15 AF XY: 0.00861 AC XY: 1167 AN XY: 135582

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.0268

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00735

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.00906

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.00790 AC: 11549 AN: 1461058 Hom.: 70 Cov.: 32 AF XY: 0.00789 AC XY: 5738 AN XY: 726792

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.0277

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00701

Gnomad4 FIN exome AF: 0.0157

Gnomad4 NFE exome AF: 0.00775

Gnomad4 OTH exome AF: 0.00896

GnomAD4 genome AF: 0.00746 AC: 1136 AN: 152340 Hom.: 10 Cov.: 32 AF XY: 0.00780 AC XY: 581 AN XY: 74486

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0211

Gnomad4 NFE AF: 0.00928

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00933 Hom.: 4

Bravo AF: 0.00605

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 17, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCA3: BP4, BS2 -

Interstitial lung disease due to ABCA3 deficiency Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Feb 03, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.4165-8G>A in intron 27 of ABCA3: This variant is not expected to have clinical significance because it has been identified in 2% (677/66082) of European chrom osomes, including 7 homozygotes by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs138769732). -

Hereditary pulmonary alveolar proteinosis Benign:1

Sep 18, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000092
dbscSNV1_RF	Benign	0.024
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

LitVar

Other links and lift over

dbSNP: rs138769732; hg19: chr16-2331230;