9-104806424-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.4281G>A(p.Thr1427Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,613,794 control chromosomes in the GnomAD database, including 8,648 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. T1427T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.087 ( 824 hom., cov: 32)

Exomes 𝑓: 0.091 ( 7824 hom. )

Consequence

ABCA1
NM_005502.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.190

Publications

33 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
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=-0.65).

BP6

Variant 9-104806424-C-T is Benign according to our data. Variant chr9-104806424-C-T is described in ClinVar as Benign. ClinVar VariationId is 364402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.19 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005502.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.4281G>A	p.Thr1427Thr	synonymous	Exon 31 of 50	NP_005493.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.4281G>A	p.Thr1427Thr	synonymous	Exon 31 of 50	ENSP00000363868.3	O95477
	ABCA1	ENST00000678995.1		c.4287G>A	p.Thr1429Thr	synonymous	Exon 31 of 50	ENSP00000504612.1	A0A7I2V5U0

Frequencies

GnomAD3 genomes

AF:

0.0870

AC:

13222

AN:

152020

Hom.:

824

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0353

Gnomad AMI

AF:

0.0648

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.122

Gnomad EAS

AF:

0.294

Gnomad SAS

AF:

0.0583

Gnomad FIN

AF:

0.0544

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0836

Gnomad OTH

AF:

0.113

GnomAD2 exomes

AF:

0.114

AC:

28704

AN:

250980

AF XY:

0.108

show subpopulations

Gnomad AFR exome

AF:

0.0312

Gnomad AMR exome

AF:

0.240

Gnomad ASJ exome

AF:

0.135

Gnomad EAS exome

AF:

0.287

Gnomad FIN exome

AF:

0.0565

Gnomad NFE exome

AF:

0.0862

Gnomad OTH exome

AF:

0.109

GnomAD4 exome

AF:

0.0911

AC:

133201

AN:

1461656

Hom.:

7824

Cov.:

AF XY:

0.0897

AC XY:

65255

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.0324

AC:

1085

AN:

33480

American (AMR)

AF:

0.236

AC:

10547

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.137

AC:

3570

AN:

26134

East Asian (EAS)

AF:

0.292

AC:

11591

AN:

39694

South Asian (SAS)

AF:

0.0557

AC:

4804

AN:

86246

European-Finnish (FIN)

AF:

0.0569

AC:

3036

AN:

53380

Middle Eastern (MID)

AF:

0.0856

AC:

494

AN:

5768

European-Non Finnish (NFE)

AF:

0.0831

AC:

92409

AN:

1111864

Other (OTH)

AF:

0.0938

AC:

5665

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

6227

12455

18682

24910

31137

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3562

7124

10686

14248

17810

<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:

0.0869

AC:

13227

AN:

152138

Hom.:

824

Cov.:

AF XY:

0.0887

AC XY:

6599

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0352

AC:

1464

AN:

41534

American (AMR)

AF:

0.194

AC:

2963

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.122

AC:

424

AN:

3470

East Asian (EAS)

AF:

0.294

AC:

1511

AN:

5148

South Asian (SAS)

AF:

0.0583

AC:

281

AN:

4816

European-Finnish (FIN)

AF:

0.0544

AC:

576

AN:

10592

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0836

AC:

5683

AN:

67970

Other (OTH)

AF:

0.113

AC:

239

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

597

1195

1792

2390

2987

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<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:

0.0905

Hom.:

2456

Bravo

AF:

0.0994

Asia WGS

AF:

0.161

AC:

560

AN:

3478

EpiCase

AF:

0.0899

EpiControl

AF:

0.0915

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Cardiovascular phenotype (1)

Hypoalphalipoproteinemia, primary, 1 (1)

Tangier disease (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

5.4

(source)

DANN

Benign

0.41

PhyloP100

-0.19

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=98/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over