9-104826974-C-T

Position:

chr9-104826974-C-T

Variant summary

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

The NM_005502.4(ABCA1):c.2311G>A(p.Val771Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0394 in 1,613,990 control chromosomes in the GnomAD database, including 1,908 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. V771L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.058 ( 346 hom., cov: 33)

Exomes 𝑓: 0.037 ( 1562 hom. )

Consequence

ABCA1
NM_005502.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.80

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=0.0017911494).

BP6

Variant 9-104826974-C-T is Benign according to our data. Variant chr9-104826974-C-T is described in ClinVar as [Benign]. Clinvar id is 364433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104826974-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA1	NM_005502.4 linkuse as main transcript	c.2311G>A	p.Val771Met	missense_variant	16/50	ENST00000374736.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ABCA1	ENST00000374736.8 linkuse as main transcript	c.2311G>A	p.Val771Met	missense_variant	16/50	1	NM_005502.4	P1
ABCA1	ENST00000678995.1 linkuse as main transcript	c.2311G>A	p.Val771Met	missense_variant	16/50
ABCA1	ENST00000494467.1 linkuse as main transcript	n.484G>A		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes

AF:

0.0580

AC:

8824

AN:

152138

Hom.:

347

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0946

Gnomad AMI

AF:

0.155

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.0533

Gnomad EAS

AF:

0.0269

Gnomad SAS

AF:

0.0634

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0315

Gnomad OTH

AF:

0.0689

GnomAD3 exomes

AF:

0.0541

AC:

13584

AN:

250888

Hom.:

633

AF XY:

0.0518

AC XY:

7030

AN XY:

135656

show subpopulations

Gnomad AFR exome

AF:

0.0949

Gnomad AMR exome

AF:

0.138

Gnomad ASJ exome

AF:

0.0500

Gnomad EAS exome

AF:

0.0196

Gnomad SAS exome

AF:

0.0641

Gnomad FIN exome

AF:

0.0141

Gnomad NFE exome

AF:

0.0334

Gnomad OTH exome

AF:

0.0580

GnomAD4 exome

AF:

0.0374

AC:

54721

AN:

1461734

Hom.:

1562

Cov.:

AF XY:

0.0379

AC XY:

27543

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0892

Gnomad4 AMR exome

AF:

0.136

Gnomad4 ASJ exome

AF:

0.0492

Gnomad4 EAS exome

AF:

0.0426

Gnomad4 SAS exome

AF:

0.0640

Gnomad4 FIN exome

AF:

0.0160

Gnomad4 NFE exome

AF:

0.0297

Gnomad4 OTH exome

AF:

0.0462

GnomAD4 genome

AF:

0.0580

AC:

8835

AN:

152256

Hom.:

346

Cov.:

AF XY:

0.0585

AC XY:

4360

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0945

Gnomad4 AMR

AF:

0.109

Gnomad4 ASJ

AF:

0.0533

Gnomad4 EAS

AF:

0.0272

Gnomad4 SAS

AF:

0.0632

Gnomad4 FIN

AF:

0.0136

Gnomad4 NFE

AF:

0.0315

Gnomad4 OTH

AF:

0.0691

Alfa

AF:

0.0357

Hom.:

214

Bravo

AF:

0.0662

TwinsUK

AF:

0.0267

AC:

ALSPAC

AF:

0.0278

AC:

107

ESP6500AA

AF:

0.0915

AC:

403

ESP6500EA

AF:

0.0363

AC:

312

ExAC

AF:

0.0512

AC:

6210

EpiCase

AF:

0.0365

EpiControl

AF:

0.0344

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	This variant is associated with the following publications: (PMID: 15520867, 24503134) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 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

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.097

DEOGEN2

Benign

0.31

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.47

MutationTaster

Benign

0.0024

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.65

REVEL

Benign

0.18

Sift

Benign

0.78

Sift4G

Benign

1.0

Polyphen

0.074

Vest4

0.086

MPC

0.27

ClinPred

0.0074

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.33

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