9-104817351-C-G

Position:

chr9-104817351-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005502.4(ABCA1):c.3516G>C(p.Glu1172Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,614,132 control chromosomes in the GnomAD database, including 1,919 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1172G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.069 ( 686 hom., cov: 32)

Exomes 𝑓: 0.032 ( 1233 hom. )

Consequence

ABCA1
NM_005502.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.898

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016642511).

BP6

Variant 9-104817351-C-G is Benign according to our data. Variant chr9-104817351-C-G is described in ClinVar as [Benign]. Clinvar id is 364416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104817351-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 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.3516G>C	p.Glu1172Asp	missense_variant	24/50	ENST00000374736.8	NP_005493.2	O95477B7XCW9B2RUU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8 linkuse as main transcript	c.3516G>C	p.Glu1172Asp	missense_variant	24/50	1	NM_005502.4	ENSP00000363868.3		O95477
ABCA1	ENST00000678995.1 linkuse as main transcript	c.3463-47G>C		intron_variant				ENSP00000504612.1		A0A7I2V5U0

Frequencies

GnomAD3 genomes

AF:

0.0687

AC:

10455

AN:

152150

Hom.:

686

Cov.:

show subpopulations

Gnomad AFR

AF:

0.173

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0393

Gnomad ASJ

AF:

0.0415

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.0271

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0294

Gnomad OTH

AF:

0.0631

GnomAD3 exomes

AF:

0.0348

AC:

8752

AN:

251472

Hom.:

334

AF XY:

0.0320

AC XY:

4351

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.175

Gnomad AMR exome

AF:

0.0202

Gnomad ASJ exome

AF:

0.0379

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0246

Gnomad FIN exome

AF:

0.0250

Gnomad NFE exome

AF:

0.0291

Gnomad OTH exome

AF:

0.0353

GnomAD4 exome

AF:

0.0323

AC:

47163

AN:

1461864

Hom.:

1233

Cov.:

AF XY:

0.0315

AC XY:

22912

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.177

Gnomad4 AMR exome

AF:

0.0217

Gnomad4 ASJ exome

AF:

0.0412

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0223

Gnomad4 FIN exome

AF:

0.0247

Gnomad4 NFE exome

AF:

0.0298

Gnomad4 OTH exome

AF:

0.0395

GnomAD4 genome

AF:

0.0688

AC:

10471

AN:

152268

Hom.:

686

Cov.:

AF XY:

0.0667

AC XY:

4963

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.173

Gnomad4 AMR

AF:

0.0392

Gnomad4 ASJ

AF:

0.0415

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0168

Gnomad4 FIN

AF:

0.0271

Gnomad4 NFE

AF:

0.0294

Gnomad4 OTH

AF:

0.0624

Alfa

AF:

0.0345

Hom.:

126

Bravo

AF:

0.0735

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0231

AC:

ESP6500AA

AF:

0.161

AC:

710

ESP6500EA

AF:

0.0317

AC:

273

ExAC

AF:

0.0382

AC:

4636

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0322

EpiControl

AF:

0.0298

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 01, 2018	This variant is associated with the following publications: (PMID: 11257261, 24503134, 20880529) -

ABCA1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 01, 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

Apr 30, 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. -

Tangier disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Hypoalphalipoproteinemia, primary, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.30

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.78

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.7

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.49

REVEL

Uncertain

0.33

Sift

Benign

0.32

Sift4G

Benign

0.52

Polyphen

0.0010

Vest4

0.23

MutPred

0.25

Loss of sheet (P = 0.0315);

MPC

0.34

ClinPred

0.0074

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.45

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