rs9282541

chr9-104858554-G-A

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.688C>T(p.Arg230Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00286 in 1,614,124 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts 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. R230H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (202 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.37

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=0.0035909414).
• BP6: Variant 9-104858554-G-A is Benign according to our data. Variant chr9-104858554-G-A is described in ClinVar as [Benign]. Clinvar id is 364456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-104858554-G-A is described in Lovd as [Likely_benign]. Variant chr9-104858554-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA1	NM_005502.4	c.688C>T	p.Arg230Cys	missense_variant	7/50	ENST00000374736.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA1	ENST00000374736.8	c.688C>T	p.Arg230Cys	missense_variant	7/50	1	NM_005502.4	P1
ABCA1	ENST00000678995.1	c.688C>T	p.Arg230Cys	missense_variant	7/50
ABCA1	ENST00000423487.6	c.688C>T	p.Arg230Cys	missense_variant	7/8	2

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 693 AN: 152194 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.0127 AC: 3197 AN: 251490 Hom.: 182 AF XY: 0.00940 AC XY: 1277 AN XY: 135920

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.0905

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00269 AC: 3931 AN: 1461812 Hom.: 202 Cov.: 31 AF XY: 0.00222 AC XY: 1616 AN XY: 727206

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.0839

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000459

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00454 AC: 692 AN: 152312 Hom.: 24 Cov.: 32 AF XY: 0.00485 AC XY: 361 AN XY: 74486

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.0415

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000849 Hom.: 8

Bravo AF: 0.00926

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00889 AC: 1079

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2019	This variant is associated with the following publications: (PMID: 28870971, 21315358, 18003760, 22995991, 20418488, 23273975, 20797885, 23152888, 10938021, 26579206, 27535533, 31006134, 31010439) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Tangier disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Nov 01, 2023	- -

ABCA1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 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

Mar 22, 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 28, 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	0.17
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Uncertain	24
Dann	Benign	0.94
DEOGEN2	Uncertain	0.44	T;T
Eigen	Benign	-0.024
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.49	N;N
REVEL	Uncertain	0.47
Sift	Benign	0.14	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0	B;.
Vest4		0.59
MPC		0.24
ClinPred		0.0087	T
GERP RS		5.1
Varity_R		0.13
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

Other links and lift over

dbSNP: rs9282541; hg19: chr9-107620835; COSMIC: COSV66057527; COSMIC: COSV66057527;