NM_005502.4:c.-18G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_005502.4(ABCA1):c.-18G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,571,042 control chromosomes in the GnomAD database, including 14,702 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 1173 hom., cov: 32)

Exomes 𝑓: 0.13 ( 13529 hom. )

Consequence

ABCA1
NM_005502.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.332

Publications

58 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 -18 ACMG points.

BP4

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

BP6

Variant 9-104903697-C-G is Benign according to our data. Variant chr9-104903697-C-G is described in ClinVar as Benign. ClinVar VariationId is 364468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4 link	c.-18G>C		5_prime_UTR_variant	Exon 2 of 50	ENST00000374736.8	NP_005493.2	O95477B7XCW9B2RUU2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCA1	ENST00000374736.8 link	c.-18G>C	5_prime_UTR_variant	Exon 2 of 50	1	NM_005502.4	ENSP00000363868.3	O95477
ABCA1	ENST00000678995.1 link	c.-18G>C	5_prime_UTR_variant	Exon 2 of 50			ENSP00000504612.1	A0A7I2V5U0
ABCA1	ENST00000423487.6 link	c.-18G>C	5_prime_UTR_variant	Exon 2 of 8	2		ENSP00000416623.2	B1AMI2
ABCA1	ENST00000374733.1 link	c.-114-14502G>C	intron_variant	Intron 1 of 4	2		ENSP00000363865.1	B1AMI1

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16213

AN:

152158

Hom.:

1171

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0252

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.158

Gnomad ASJ

AF:

0.144

Gnomad EAS

AF:

0.182

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.112

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.127

Gnomad OTH

AF:

0.112

GnomAD2 exomes

AF:

0.145

AC:

26746

AN:

184886

AF XY:

0.148

show subpopulations

Gnomad AFR exome

AF:

0.0231

Gnomad AMR exome

AF:

0.199

Gnomad ASJ exome

AF:

0.148

Gnomad EAS exome

AF:

0.168

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.121

Gnomad OTH exome

AF:

0.145

GnomAD4 exome

AF:

0.132

AC:

187609

AN:

1418766

Hom.:

13529

Cov.:

AF XY:

0.135

AC XY:

94748

AN XY:

701630

show subpopulations

African (AFR)

AF:

0.0194

AC:

632

AN:

32650

American (AMR)

AF:

0.190

AC:

7228

AN:

37966

Ashkenazi Jewish (ASJ)

AF:

0.150

AC:

3801

AN:

25368

East Asian (EAS)

AF:

0.195

AC:

7344

AN:

37692

South Asian (SAS)

AF:

0.225

AC:

18154

AN:

80844

European-Finnish (FIN)

AF:

0.105

AC:

5286

AN:

50358

Middle Eastern (MID)

AF:

0.118

AC:

672

AN:

5698

European-Non Finnish (NFE)

AF:

0.125

AC:

136135

AN:

1089358

Other (OTH)

AF:

0.142

AC:

8357

AN:

58832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

8249

16498

24748

32997

41246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5082

10164

15246

20328

25410

<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:

0.107

AC:

16227

AN:

152276

Hom.:

1173

Cov.:

AF XY:

0.110

AC XY:

8163

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0251

AC:

1043

AN:

41562

American (AMR)

AF:

0.158

AC:

2421

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

500

AN:

3470

East Asian (EAS)

AF:

0.182

AC:

938

AN:

5166

South Asian (SAS)

AF:

0.242

AC:

1170

AN:

4832

European-Finnish (FIN)

AF:

0.112

AC:

1186

AN:

10616

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.127

AC:

8633

AN:

68020

Other (OTH)

AF:

0.119

AC:

251

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

773

1546

2318

3091

3864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

384

576

768

960

<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:

0.0757

Hom.:

116

Bravo

AF:

0.106

Asia WGS

AF:

0.217

AC:

751

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 01, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Sep 20, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Tangier disease

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. -

Hypoalphalipoproteinemia, primary, 1

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

(source)

DANN

Benign

0.85

PhyloP100

0.33

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=97/3

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