rs35871586

Positions:

chr9-104819668-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005502.4(ABCA1):c.3159T>G(p.Val1053Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00999 in 1,614,208 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 3 hom., cov: 32)

Exomes 𝑓: 0.010 ( 98 hom. )

Consequence

ABCA1
NM_005502.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.148

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 9-104819668-A-C is Benign according to our data. Variant chr9-104819668-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 364421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104819668-A-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.148 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00735 (1119/152314) while in subpopulation NFE AF= 0.0118 (801/68022). AF 95% confidence interval is 0.0111. There are 3 homozygotes in gnomad4. There are 505 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA1	NM_005502.4 link	c.3159T>G	p.Val1053Val	synonymous_variant	22/50	ENST00000374736.8	NP_005493.2	O95477B7XCW9B2RUU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8 link	c.3159T>G	p.Val1053Val	synonymous_variant	22/50	1	NM_005502.4	ENSP00000363868.3		O95477
ABCA1	ENST00000678995.1 link	c.3159T>G	p.Val1053Val	synonymous_variant	22/50			ENSP00000504612.1		A0A7I2V5U0

Frequencies

GnomAD3 genomes

AF:

0.00735

AC:

1119

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00510

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.00750

AC:

1887

AN:

251452

Hom.:

AF XY:

0.00746

AC XY:

1014

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00178

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00421

Gnomad FIN exome

AF:

0.0115

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.00961

GnomAD4 exome

AF:

0.0103

AC:

15012

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0100

AC XY:

7273

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.00434

Gnomad4 ASJ exome

AF:

0.00168

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00428

Gnomad4 FIN exome

AF:

0.0116

Gnomad4 NFE exome

AF:

0.0118

Gnomad4 OTH exome

AF:

0.00922

GnomAD4 genome

AF:

0.00735

AC:

1119

AN:

152314

Hom.:

Cov.:

AF XY:

0.00678

AC XY:

505

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00331

Gnomad4 FIN

AF:

0.0105

Gnomad4 NFE

AF:

0.0118

Gnomad4 OTH

AF:

0.00804

Alfa

AF:

0.00872

Hom.:

Bravo

AF:

0.00648

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0101

EpiControl

AF:

0.0108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 30, 2016	Variant summary: The ABCA1 c.3159T>G (p.Val1053Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 918/121410 control chromosomes (including 6 homozygotes) at a frequency of 0.0075612, which is approximately 605 times the estimated maximal expected allele frequency of a pathogenic ABCA1 variant (0.0000125), suggesting this variant is a benign polymorphism. One internal sample carrying this variant also carries another deleterious variant PCSK9 p.Tyr142X further supporting for benign outcome. Taken together, this variant is classified as Benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ABCA1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2019

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.6

DANN

Benign

0.74

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over