16-2319773-G-A

Position:

chr16-2319773-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001089.3(ABCA3):c.681C>T(p.Ala227Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 1,613,952 control chromosomes in the GnomAD database, including 412 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 34 hom., cov: 30)

Exomes 𝑓: 0.021 ( 378 hom. )

Consequence

ABCA3
NM_001089.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.370

Variant links:

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 links:

ABCA3 (HGNC:):

ABCA3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 16-2319773-G-A is Benign according to our data. Variant chr16-2319773-G-A is described in ClinVar as [Benign]. Clinvar id is 162673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2319773-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.37 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0165 (2516/152160) while in subpopulation SAS AF= 0.0214 (103/4816). AF 95% confidence interval is 0.0201. There are 34 homozygotes in gnomad4. There are 1284 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA3	NM_001089.3 linkuse as main transcript	c.681C>T	p.Ala227Ala	synonymous_variant	8/33	ENST00000301732.10	NP_001080.2	Q99758-1Q4LE27

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ABCA3	ENST00000301732.10 linkuse as main transcript	c.681C>T	p.Ala227Ala	synonymous_variant	8/33	1	NM_001089.3	ENSP00000301732.5	Q99758-1
ABCA3	ENST00000382381.7 linkuse as main transcript	c.681C>T	p.Ala227Ala	synonymous_variant	8/32	1		ENSP00000371818.3	H0Y3H2
ABCA3	ENST00000563623.5 linkuse as main transcript	n.1244C>T		non_coding_transcript_exon_variant	8/20	1

Frequencies

GnomAD3 genomes

AF:

0.0165

AC:

2514

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00357

Gnomad AMI

AF:

0.0518

Gnomad AMR

AF:

0.0161

Gnomad ASJ

AF:

0.0210

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0210

Gnomad FIN

AF:

0.0402

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0210

Gnomad OTH

AF:

0.0167

GnomAD3 exomes

AF:

0.0185

AC:

4641

AN:

251126

Hom.:

AF XY:

0.0199

AC XY:

2698

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.00333

Gnomad AMR exome

AF:

0.00633

Gnomad ASJ exome

AF:

0.0231

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0212

Gnomad FIN exome

AF:

0.0368

Gnomad NFE exome

AF:

0.0226

Gnomad OTH exome

AF:

0.0207

GnomAD4 exome

AF:

0.0214

AC:

31283

AN:

1461792

Hom.:

378

Cov.:

AF XY:

0.0216

AC XY:

15715

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00284

Gnomad4 AMR exome

AF:

0.00756

Gnomad4 ASJ exome

AF:

0.0233

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0211

Gnomad4 FIN exome

AF:

0.0371

Gnomad4 NFE exome

AF:

0.0225

Gnomad4 OTH exome

AF:

0.0209

GnomAD4 genome

AF:

0.0165

AC:

2516

AN:

152160

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1284

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00356

Gnomad4 AMR

AF:

0.0161

Gnomad4 ASJ

AF:

0.0210

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.0214

Gnomad4 FIN

AF:

0.0402

Gnomad4 NFE

AF:

0.0210

Gnomad4 OTH

AF:

0.0165

Alfa

AF:

0.0184

Hom.:

Bravo

AF:

0.0144

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0219

EpiControl

AF:

0.0201

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Ala227Ala in exon 8 of ABCA3: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 2.2% (192/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs45480502). -

Interstitial lung disease due to ABCA3 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary pulmonary alveolar proteinosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 13, 2019

This alteration is classified as 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

-0.90

CADD

Benign

0.92

DANN

Benign

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over