chr16-2295664-G-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_001089.3(ABCA3):​c.2340C>T​(p.His780His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000546 in 1,614,076 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00045 ( 1 hom. )

Consequence

ABCA3
NM_001089.3 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: -0.149
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]

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 16-2295664-G-A is Benign according to our data. Variant chr16-2295664-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 596957.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2, Benign=1}.
BP7
Synonymous conserved (PhyloP=-0.149 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00147 (224/152392) while in subpopulation AFR AF = 0.00464 (193/41598). AF 95% confidence interval is 0.0041. There are 0 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCA3NM_001089.3 linkc.2340C>T p.His780His synonymous_variant Exon 18 of 33 ENST00000301732.10 NP_001080.2 Q99758-1Q4LE27

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCA3ENST00000301732.10 linkc.2340C>T p.His780His synonymous_variant Exon 18 of 33 1 NM_001089.3 ENSP00000301732.5 Q99758-1
ABCA3ENST00000382381.7 linkc.2166C>T p.His722His synonymous_variant Exon 17 of 32 1 ENSP00000371818.3 H0Y3H2
ABCA3ENST00000563623.5 linkn.2903C>T non_coding_transcript_exon_variant Exon 18 of 20 1

Frequencies

GnomAD3 genomes
AF:
0.00147
AC:
224
AN:
152274
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00465
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000523
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000279
Gnomad OTH
AF:
0.000957
GnomAD2 exomes
AF:
0.000490
AC:
123
AN:
251178
AF XY:
0.000368
show subpopulations
Gnomad AFR exome
AF:
0.00480
Gnomad AMR exome
AF:
0.000231
Gnomad ASJ exome
AF:
0.0000992
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000300
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000449
AC:
657
AN:
1461684
Hom.:
1
Cov.:
32
AF XY:
0.000377
AC XY:
274
AN XY:
727150
show subpopulations
Gnomad4 AFR exome
AF:
0.00541
AC:
181
AN:
33480
Gnomad4 AMR exome
AF:
0.000268
AC:
12
AN:
44724
Gnomad4 ASJ exome
AF:
0.0000383
AC:
1
AN:
26136
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39700
Gnomad4 SAS exome
AF:
0.0000348
AC:
3
AN:
86258
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53210
Gnomad4 NFE exome
AF:
0.000385
AC:
428
AN:
1112012
Gnomad4 Remaining exome
AF:
0.000513
AC:
31
AN:
60396
Heterozygous variant carriers
0
43
87
130
174
217
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
22
44
66
88
110
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00147
AC:
224
AN:
152392
Hom.:
0
Cov.:
32
AF XY:
0.00126
AC XY:
94
AN XY:
74524
show subpopulations
Gnomad4 AFR
AF:
0.00464
AC:
0.00463965
AN:
0.00463965
Gnomad4 AMR
AF:
0.000522
AC:
0.000522398
AN:
0.000522398
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.000207
AC:
0.000206954
AN:
0.000206954
Gnomad4 FIN
AF:
0.0000941
AC:
0.0000940734
AN:
0.0000940734
Gnomad4 NFE
AF:
0.000279
AC:
0.000279239
AN:
0.000279239
Gnomad4 OTH
AF:
0.000947
AC:
0.00094697
AN:
0.00094697
Heterozygous variant carriers
0
15
30
45
60
75
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00113
Hom.:
0
Bravo
AF:
0.00170
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000382
EpiControl
AF:
0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency Uncertain:1Benign:1
Jan 30, 2019
Johns Hopkins Genomics, Johns Hopkins University
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This ABCA3 variant (rs45620539) has been identified in large population datasets and the minor allele frequency is neither low enough to consider the variant rare (>0.1%) nor high enough to consider it a population polymorphism (>1%) within the African subpopulation (gnomAD: 115/24972 alleles; 0.46%, no homozygotes). This patient's ethnicity is not reported. A single submitter in ClinVar classifies this variant as uncertain clinical significance (Variation ID: 596957). This variant is reported to be present in one individual with neonatal respiratory distress syndrome (RDS) and absent in an individual without RDS. Bioinformatic analysis predicts that this synonymous variant would not affect normal exon 18 splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence that this variant is deleterious, the clinical significance of c.2340C>T is uncertain at this time. -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Uncertain:1Benign:1
May 05, 2018
Eurofins Ntd Llc (ga)
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Dec 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary pulmonary alveolar proteinosis Benign:1
Nov 07, 2022
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely 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
-0.86
CADD
Benign
3.0
DANN
Benign
0.55
Mutation Taster
=100/0
polymorphism

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

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

Other links and lift over

dbSNP: rs45620539; hg19: chr16-2345665; API