16-2281429-A-G

Position:

• chr16-2281429-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001089.3(ABCA3):​c.4116T>C​(p.Ser1372=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,613,668 control chromosomes in the GnomAD database, including 674,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59447 hom., cov: 32)
  • Exomes 𝑓: 0.92 (614736 hom.)
• Consequence: ABCA3 NM_001089.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.158

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-2281429-A-G is Benign according to our data. Variant chr16-2281429-A-G is described in ClinVar as [Benign]. Clinvar id is 162672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2281429-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.158 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA3	NM_001089.3	c.4116T>C	p.Ser1372=	synonymous_variant	27/33	ENST00000301732.10	NP_001080.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA3	ENST00000301732.10	c.4116T>C	p.Ser1372=	synonymous_variant	27/33	1	NM_001089.3	ENSP00000301732	P1
ABCA3	ENST00000382381.7	c.3942T>C	p.Ser1314=	synonymous_variant	26/32	1		ENSP00000371818
ABCA3	ENST00000566200.1	n.637T>C		non_coding_transcript_exon_variant	2/5	3
ABCA3	ENST00000569062.1	n.864T>C		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.881 AC: 134071 AN: 152130 Hom.: 59400 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.977

Gnomad AMR AF: 0.914

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.953

Gnomad FIN AF: 0.957

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.910

Gnomad OTH AF: 0.893

GnomAD3 exomes AF: 0.923 AC: 231790 AN: 251228 Hom.: 107217 AF XY: 0.924 AC XY: 125555 AN XY: 135834

Gnomad AFR exome AF: 0.778

Gnomad AMR exome AF: 0.943

Gnomad ASJ exome AF: 0.908

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.954

Gnomad FIN exome AF: 0.958

Gnomad NFE exome AF: 0.911

Gnomad OTH exome AF: 0.916

GnomAD4 exome AF: 0.917 AC: 1339502 AN: 1461420 Hom.: 614736 Cov.: 70 AF XY: 0.918 AC XY: 667028 AN XY: 726992

Gnomad4 AFR exome AF: 0.773

Gnomad4 AMR exome AF: 0.941

Gnomad4 ASJ exome AF: 0.910

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.953

Gnomad4 FIN exome AF: 0.956

Gnomad4 NFE exome AF: 0.913

Gnomad4 OTH exome AF: 0.911

GnomAD4 genome AF: 0.881 AC: 134172 AN: 152248 Hom.: 59447 Cov.: 32 AF XY: 0.886 AC XY: 65964 AN XY: 74480

Gnomad4 AFR AF: 0.774

Gnomad4 AMR AF: 0.915

Gnomad4 ASJ AF: 0.904

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.952

Gnomad4 FIN AF: 0.957

Gnomad4 NFE AF: 0.910

Gnomad4 OTH AF: 0.894

Alfa AF: 0.898 Hom.: 78814

Bravo AF: 0.874

Asia WGS AF: 0.966 AC: 3360 AN: 3478

EpiCase AF: 0.903

EpiControl AF: 0.902

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Ser1372Ser in exon 27 of ABCA3: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 22.0% (968/4396) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs149532). -

Interstitial lung disease due to ABCA3 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.8
DANN	Benign	0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs149532; hg19: chr16-2331430; COSMIC: COSV57057418;