16-2323702-G-C

Variant names:

• chr16-2323702-G-C
• rs62040683
• NM_001089.3:c.448-14C>G

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.448-14C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,614,040 control chromosomes in the GnomAD database, including 299 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (17 hom., cov: 32)
  • Exomes 𝑓: 0.018 (282 hom.)
• Consequence: ABCA3 NM_001089.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.724
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-2323702-G-C is Benign according to our data. Variant chr16-2323702-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 318572.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 = 0.0131 (1996/152324) while in subpopulation NFE AF = 0.0199 (1355/68018). AF 95% confidence interval is 0.019. There are 17 homozygotes in GnomAd4. There are 958 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.448-14C>G		intron	N/A	NP_001080.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA3	ENST00000301732.10	TSL:1 MANE Select	c.448-14C>G		intron	N/A	ENSP00000301732.5
	ABCA3	ENST00000382381.7	TSL:1	c.448-14C>G		intron	N/A	ENSP00000371818.3
	ABCA3	ENST00000567910.1	TSL:1	c.448-14C>G		intron	N/A	ENSP00000454397.1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1996 AN: 152206 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0370

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.0145 AC: 3655 AN: 251414 AF XY: 0.0143

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0388

Gnomad NFE exome AF: 0.0225

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0175 AC: 25645 AN: 1461716 Hom.: 282 Cov.: 31 AF XY: 0.0173 AC XY: 12567 AN XY: 727164

African (AFR) AF: 0.00284 AC: 95 AN: 33480

American (AMR) AF: 0.00353 AC: 158 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86242

European-Finnish (FIN) AF: 0.0403 AC: 2154 AN: 53408

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5764

European-Non Finnish (NFE) AF: 0.0201 AC: 22354 AN: 1111892

Other (OTH) AF: 0.0135 AC: 815 AN: 60378

GnomAD4 genome AF: 0.0131 AC: 1996 AN: 152324 Hom.: 17 Cov.: 32 AF XY: 0.0129 AC XY: 958 AN XY: 74484

African (AFR) AF: 0.00322 AC: 134 AN: 41588

American (AMR) AF: 0.00490 AC: 75 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.0370 AC: 393 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0199 AC: 1355 AN: 68018

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.0158 Hom.: 6

Bravo AF: 0.0104

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Interstitial lung disease due to ABCA3 deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.51
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62040683; hg19: chr16-2373703;