rs2066714

Positions:

• chr9-104824472-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005502.4(ABCA1):​c.2649A>G​(p.Ile883Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,613,862 control chromosomes in the GnomAD database, including 33,696 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. I883V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.25 (7196 hom., cov: 32)
  • Exomes 𝑓: 0.16 (26500 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.873

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.671956E-6).
• BP6: Variant 9-104824472-T-C is Benign according to our data. Variant chr9-104824472-T-C is described in ClinVar as [Benign]. Clinvar id is 364426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104824472-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA1	NM_005502.4	c.2649A>G	p.Ile883Met	missense_variant	18/50	ENST00000374736.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA1	ENST00000374736.8	c.2649A>G	p.Ile883Met	missense_variant	18/50	1	NM_005502.4	P1
ABCA1	ENST00000678995.1	c.2649A>G	p.Ile883Met	missense_variant	18/50

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38593 AN: 151990 Hom.: 7177 Cov.: 32

Gnomad AFR AF: 0.477

Gnomad AMI AF: 0.0923

Gnomad AMR AF: 0.219

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.248

GnomAD3 exomes AF: 0.211 AC: 53126 AN: 251362 Hom.: 9257 AF XY: 0.198 AC XY: 26918 AN XY: 135866

Gnomad AFR exome AF: 0.480

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.718

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.158 AC: 230954 AN: 1461756 Hom.: 26500 Cov.: 33 AF XY: 0.156 AC XY: 113725 AN XY: 727188

Gnomad4 AFR exome AF: 0.492

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.663

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.0973

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.193

GnomAD4 genome AF: 0.254 AC: 38670 AN: 152106 Hom.: 7196 Cov.: 32 AF XY: 0.253 AC XY: 18846 AN XY: 74366

Gnomad4 AFR AF: 0.477

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.694

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.252

Alfa AF: 0.172 Hom.: 6478

Bravo AF: 0.281

TwinsUK AF: 0.121 AC: 449

ALSPAC AF: 0.123 AC: 473

ESP6500AA AF: 0.464 AC: 2045

ESP6500EA AF: 0.134 AC: 1154

ExAC AF: 0.213 AC: 25882

Asia WGS AF: 0.401 AC: 1394 AN: 3478

EpiCase AF: 0.132

EpiControl AF: 0.139

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2018	This variant is associated with the following publications: (PMID: 24466114, 31006134, 26243156, 27884173, 10431237, 21300560, 11238261, 17951323, 17923263) -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 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). 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. -

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). 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	0.063
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.79
DANN	Benign	0.28
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.028	T
MetaRNN	Benign	0.0000027	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.16
Sift	Benign	0.15	T
Sift4G	Benign	0.11	T
Polyphen		0.0020	B
Vest4		0.022
MPC		1.1
ClinPred		0.00040	T
GERP RS		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.39

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

Other links and lift over

dbSNP: rs2066714; hg19: chr9-107586753; COSMIC: COSV66065926; COSMIC: COSV66065926;