rs13332514

chr16-2317335-G-A

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.1059C>T(p.Phe353=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,613,880 control chromosomes in the GnomAD database, including 16,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1626 hom., cov: 31)
  • Exomes 𝑓: 0.12 (14864 hom.)
• Consequence: ABCA3 NM_001089.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.597

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=-0.47).
• BP6: Variant 16-2317335-G-A is Benign according to our data. Variant chr16-2317335-G-A is described in ClinVar as [Benign]. Clinvar id is 178698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.597 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA3	NM_001089.3	c.1059C>T	p.Phe353=	synonymous_variant	10/33	ENST00000301732.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA3	ENST00000301732.10	c.1059C>T	p.Phe353=	synonymous_variant	10/33	1	NM_001089.3	P1
ABCA3	ENST00000382381.7	c.1059C>T	p.Phe353=	synonymous_variant	10/32	1
ABCA3	ENST00000563623.5	n.1622C>T		non_coding_transcript_exon_variant	10/20	1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18599 AN: 152024 Hom.: 1614 Cov.: 31

Gnomad AFR AF: 0.0861

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0927

Gnomad OTH AF: 0.134

GnomAD3 exomes AF: 0.170 AC: 42768 AN: 251266 Hom.: 5760 AF XY: 0.161 AC XY: 21865 AN XY: 135816

Gnomad AFR exome AF: 0.0847

Gnomad AMR exome AF: 0.409

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.378

Gnomad SAS exome AF: 0.177

Gnomad FIN exome AF: 0.0941

Gnomad NFE exome AF: 0.0957

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.121 AC: 176631 AN: 1461740 Hom.: 14864 Cov.: 33 AF XY: 0.121 AC XY: 87800 AN XY: 727176

Gnomad4 AFR exome AF: 0.0835

Gnomad4 AMR exome AF: 0.393

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.392

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.0914

Gnomad4 NFE exome AF: 0.0987

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.123 AC: 18646 AN: 152140 Hom.: 1626 Cov.: 31 AF XY: 0.129 AC XY: 9618 AN XY: 74374

Gnomad4 AFR AF: 0.0864

Gnomad4 AMR AF: 0.272

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.372

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0927

Gnomad4 OTH AF: 0.133

Alfa AF: 0.0982 Hom.: 461

Bravo AF: 0.136

Asia WGS AF: 0.233 AC: 811 AN: 3478

EpiCase AF: 0.0985

EpiControl AF: 0.0951

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 02, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2013

Phe353Phe in exon 10 of ABCA3: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 9.8% (847/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs13332514). -

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

Oct 14, 2015

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	-0.47
Cadd	Benign	2.1
Dann	Benign	0.51

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: rs13332514; hg19: chr16-2367336; COSMIC: COSV57053979;