rs2274873

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_005502.4(ABCA1):c.936C>T(p.Pro312=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0969 in 1,614,018 control chromosomes in the GnomAD database, including 7,922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 702 hom., cov: 32)

Exomes 𝑓: 0.097 ( 7220 hom. )

Consequence

ABCA1
NM_005502.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.18

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 9-104840397-G-A is Benign according to our data. Variant chr9-104840397-G-A is described in ClinVar as [Benign]. Clinvar id is 364451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104840397-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.18 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA1	NM_005502.4 linkuse as main transcript	c.936C>T	p.Pro312=	synonymous_variant	9/50	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8 linkuse as main transcript	c.936C>T	p.Pro312=	synonymous_variant	9/50	1	NM_005502.4	ENSP00000363868	P1
ABCA1	ENST00000678995.1 linkuse as main transcript	c.936C>T	p.Pro312=	synonymous_variant	9/50			ENSP00000504612

Frequencies

GnomAD3 genomes

AF:

0.0921

AC:

14010

AN:

152044

Hom.:

703

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0972

Gnomad AMI

AF:

0.202

Gnomad AMR

AF:

0.0578

Gnomad ASJ

AF:

0.0822

Gnomad EAS

AF:

0.0702

Gnomad SAS

AF:

0.0838

Gnomad FIN

AF:

0.0886

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0988

Gnomad OTH

AF:

0.0836

GnomAD3 exomes

AF:

0.0848

AC:

21313

AN:

251422

Hom.:

1017

AF XY:

0.0865

AC XY:

11760

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.0966

Gnomad AMR exome

AF:

0.0379

Gnomad ASJ exome

AF:

0.0864

Gnomad EAS exome

AF:

0.0671

Gnomad SAS exome

AF:

0.0895

Gnomad FIN exome

AF:

0.0819

Gnomad NFE exome

AF:

0.0993

Gnomad OTH exome

AF:

0.0844

GnomAD4 exome

AF:

0.0974

AC:

142332

AN:

1461856

Hom.:

7220

Cov.:

AF XY:

0.0974

AC XY:

70811

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.102

Gnomad4 AMR exome

AF:

0.0393

Gnomad4 ASJ exome

AF:

0.0858

Gnomad4 EAS exome

AF:

0.0917

Gnomad4 SAS exome

AF:

0.0857

Gnomad4 FIN exome

AF:

0.0832

Gnomad4 NFE exome

AF:

0.102

Gnomad4 OTH exome

AF:

0.0964

GnomAD4 genome

AF:

0.0922

AC:

14023

AN:

152162

Hom.:

702

Cov.:

AF XY:

0.0900

AC XY:

6697

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0973

Gnomad4 AMR

AF:

0.0578

Gnomad4 ASJ

AF:

0.0822

Gnomad4 EAS

AF:

0.0698

Gnomad4 SAS

AF:

0.0830

Gnomad4 FIN

AF:

0.0886

Gnomad4 NFE

AF:

0.0988

Gnomad4 OTH

AF:

0.0851

Alfa

AF:

0.0964

Hom.:

1707

Bravo

AF:

0.0893

Asia WGS

AF:

0.105

AC:

364

AN:

3478

EpiCase

AF:

0.103

EpiControl

AF:

0.0997

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ABCA1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

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. -

Tangier disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Hypoalphalipoproteinemia, primary, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.35

DANN

Benign

0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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