rs2246841

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005502.4(ABCA1):c.948G>A(p.Gly316Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,614,046 control chromosomes in the GnomAD database, including 11,625 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1871 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9754 hom. )

Consequence

ABCA1
NM_005502.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.58

Publications

21 publications found

Variant links:

Genes affected

ABCA1 (HGNC:29): (ATP binding cassette subfamily A member 1) 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. With cholesterol as its substrate, this protein functions as a cholesteral efflux pump in the cellular lipid removal pathway. Mutations in both alleles of this gene cause Tangier disease and familial high-density lipoprotein (HDL) deficiency. [provided by RefSeq, Sep 2019]

ABCA1 Gene-Disease associations (from GenCC):

hypoalphalipoproteinemia, primary, 1
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Tangier disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
apolipoprotein A-I deficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ABCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 9-104840385-C-T is Benign according to our data. Variant chr9-104840385-C-T is described in ClinVar as Benign. ClinVar VariationId is 364450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.58 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4 link	c.948G>A	p.Gly316Gly	synonymous_variant	Exon 9 of 50	ENST00000374736.8	NP_005493.2	O95477B7XCW9B2RUU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8 link	c.948G>A	p.Gly316Gly	synonymous_variant	Exon 9 of 50	1	NM_005502.4	ENSP00000363868.3		O95477
ABCA1	ENST00000678995.1 link	c.948G>A	p.Gly316Gly	synonymous_variant	Exon 9 of 50			ENSP00000504612.1		A0A7I2V5U0

Frequencies

GnomAD3 genomes

AF:

0.145

AC:

22010

AN:

152080

Hom.:

1873

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.181

Gnomad AMR

AF:

0.174

Gnomad ASJ

AF:

0.0988

Gnomad EAS

AF:

0.0276

Gnomad SAS

AF:

0.153

Gnomad FIN

AF:

0.0723

Gnomad MID

AF:

0.165

Gnomad NFE

AF:

0.106

Gnomad OTH

AF:

0.148

GnomAD2 exomes

AF:

0.122

AC:

30764

AN:

251424

AF XY:

0.121

show subpopulations

Gnomad AFR exome

AF:

0.231

Gnomad AMR exome

AF:

0.178

Gnomad ASJ exome

AF:

0.100

Gnomad EAS exome

AF:

0.0197

Gnomad FIN exome

AF:

0.0738

Gnomad NFE exome

AF:

0.108

Gnomad OTH exome

AF:

0.126

GnomAD4 exome

AF:

0.110

AC:

161130

AN:

1461848

Hom.:

9754

Cov.:

AF XY:

0.111

AC XY:

81027

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.231

AC:

7719

AN:

33478

American (AMR)

AF:

0.179

AC:

8019

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0958

AC:

2504

AN:

26136

East Asian (EAS)

AF:

0.0425

AC:

1689

AN:

39700

South Asian (SAS)

AF:

0.156

AC:

13414

AN:

86254

European-Finnish (FIN)

AF:

0.0784

AC:

4188

AN:

53416

Middle Eastern (MID)

AF:

0.174

AC:

1003

AN:

5768

European-Non Finnish (NFE)

AF:

0.104

AC:

115534

AN:

1111980

Other (OTH)

AF:

0.117

AC:

7060

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

8816

17633

26449

35266

44082

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4316

8632

12948

17264

21580

<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:

0.145

AC:

22034

AN:

152198

Hom.:

1871

Cov.:

AF XY:

0.144

AC XY:

10703

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.232

AC:

9616

AN:

41504

American (AMR)

AF:

0.174

AC:

2660

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0988

AC:

343

AN:

3470

East Asian (EAS)

AF:

0.0278

AC:

144

AN:

5174

South Asian (SAS)

AF:

0.153

AC:

736

AN:

4818

European-Finnish (FIN)

AF:

0.0723

AC:

768

AN:

10620

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.106

AC:

7243

AN:

68010

Other (OTH)

AF:

0.147

AC:

311

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

955

1910

2864

3819

4774

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

236

472

708

944

1180

<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:

0.119

Hom.:

4842

Bravo

AF:

0.154

Asia WGS

AF:

0.100

AC:

347

AN:

3478

EpiCase

AF:

0.117

EpiControl

AF:

0.112

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 30, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Feb 05, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Hypoalphalipoproteinemia, primary, 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Tangier disease

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

1.8

(source)

DANN

Benign

0.63

PhyloP100

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over