rs138769732

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr16-2281229-C-T
• chr16-2281229-C-A

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.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
• Publications: 0 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 (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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.4165-8G>A		splice_region intron	N/A	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.4165-8G>A		splice_region intron	N/A	ENSP00000301732.5	Q99758-1
	ABCA3	ENST00000382381.7	TSL:1	c.3991-8G>A		splice_region intron	N/A	ENSP00000371818.3	H0Y3H2
	ABCA3	ENST00000967440.1		c.4165-8G>A		splice_region intron	N/A	ENSP00000637499.1

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

GnomAD2 exomes AF: 0.00824 AC: 2065 AN: 250606 AF XY: 0.00861

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 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

African (AFR) AF: 0.00140 AC: 47 AN: 33480

American (AMR) AF: 0.00300 AC: 134 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0277 AC: 725 AN: 26136

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

South Asian (SAS) AF: 0.00701 AC: 605 AN: 86258

European-Finnish (FIN) AF: 0.0157 AC: 829 AN: 52692

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5768

European-Non Finnish (NFE) AF: 0.00775 AC: 8620 AN: 1111930

Other (OTH) AF: 0.00896 AC: 541 AN: 60374

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

African (AFR) AF: 0.00178 AC: 74 AN: 41590

American (AMR) AF: 0.00425 AC: 65 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4832

European-Finnish (FIN) AF: 0.0211 AC: 224 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00928 AC: 631 AN: 68028

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00937 Hom.: 8

Bravo AF: 0.00605

Asia WGS AF: 0.00173 AC: 6 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	Interstitial lung disease due to ABCA3 deficiency (2)
-	-	1	Hereditary pulmonary alveolar proteinosis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.0
DANN	Benign	0.63
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs138769732; hg19: chr16-2331230;