9-104861748-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005502.4(ABCA1):c.474G>A(p.Leu158Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,612,688 control chromosomes in the GnomAD database, including 66,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L158L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.32 ( 8536 hom., cov: 30)

Exomes 𝑓: 0.27 ( 58127 hom. )

Consequence

ABCA1
NM_005502.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.352

Publications

54 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 9-104861748-C-T is Benign according to our data. Variant chr9-104861748-C-T is described in ClinVar as Benign. ClinVar VariationId is 364460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.352 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4 link	c.474G>A	p.Leu158Leu	synonymous_variant	Exon 6 of 50	ENST00000374736.8	NP_005493.2	O95477B7XCW9B2RUU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCA1	ENST00000374736.8 link	c.474G>A	p.Leu158Leu	synonymous_variant	Exon 6 of 50	1	NM_005502.4	ENSP00000363868.3	O95477
ABCA1	ENST00000678995.1 link	c.474G>A	p.Leu158Leu	synonymous_variant	Exon 6 of 50			ENSP00000504612.1	A0A7I2V5U0
ABCA1	ENST00000423487.6 link	c.474G>A	p.Leu158Leu	synonymous_variant	Exon 6 of 8	2		ENSP00000416623.2	B1AMI2
ABCA1	ENST00000374733.1 link	c.294G>A	p.Leu98Leu	synonymous_variant	Exon 5 of 5	2		ENSP00000363865.1	B1AMI1

Frequencies

GnomAD3 genomes

AF:

0.324

AC:

49088

AN:

151292

Hom.:

8512

Cov.:

show subpopulations

Gnomad AFR

AF:

0.444

Gnomad AMI

AF:

0.444

Gnomad AMR

AF:

0.324

Gnomad ASJ

AF:

0.264

Gnomad EAS

AF:

0.408

Gnomad SAS

AF:

0.380

Gnomad FIN

AF:

0.219

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.259

Gnomad OTH

AF:

0.326

GnomAD2 exomes

AF:

0.300

AC:

75312

AN:

251444

AF XY:

0.300

show subpopulations

Gnomad AFR exome

AF:

0.445

Gnomad AMR exome

AF:

0.306

Gnomad ASJ exome

AF:

0.266

Gnomad EAS exome

AF:

0.406

Gnomad FIN exome

AF:

0.214

Gnomad NFE exome

AF:

0.259

Gnomad OTH exome

AF:

0.300

GnomAD4 exome

AF:

0.275

AC:

401833

AN:

1461278

Hom.:

58127

Cov.:

AF XY:

0.278

AC XY:

202344

AN XY:

726970

show subpopulations

African (AFR)

AF:

0.447

AC:

14956

AN:

33460

American (AMR)

AF:

0.309

AC:

13812

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

6973

AN:

26136

East Asian (EAS)

AF:

0.463

AC:

18378

AN:

39692

South Asian (SAS)

AF:

0.372

AC:

32117

AN:

86234

European-Finnish (FIN)

AF:

0.214

AC:

11428

AN:

53390

Middle Eastern (MID)

AF:

0.374

AC:

2156

AN:

5764

European-Non Finnish (NFE)

AF:

0.256

AC:

284163

AN:

1111500

Other (OTH)

AF:

0.296

AC:

17850

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

15038

30077

45115

60154

75192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9760

19520

29280

39040

48800

<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:

0.325

AC:

49165

AN:

151410

Hom.:

8536

Cov.:

AF XY:

0.326

AC XY:

24114

AN XY:

73910

show subpopulations

African (AFR)

AF:

0.444

AC:

18327

AN:

41236

American (AMR)

AF:

0.324

AC:

4923

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.264

AC:

913

AN:

3460

East Asian (EAS)

AF:

0.407

AC:

2094

AN:

5146

South Asian (SAS)

AF:

0.381

AC:

1825

AN:

4796

European-Finnish (FIN)

AF:

0.219

AC:

2269

AN:

10378

Middle Eastern (MID)

AF:

0.357

AC:

105

AN:

294

European-Non Finnish (NFE)

AF:

0.259

AC:

17610

AN:

67870

Other (OTH)

AF:

0.330

AC:

694

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1636

3272

4907

6543

8179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

486

972

1458

1944

2430

<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:

0.280

Hom.:

24042

Bravo

AF:

0.335

Asia WGS

AF:

0.383

AC:

1329

AN:

3478

EpiCase

AF:

0.276

EpiControl

AF:

0.269

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.48

CADD

Benign

6.9

(source)

DANN

Benign

0.65

PhyloP100

-0.35

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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