chr9-104800523-T-C

Variant names:

• chr9-104800523-T-C
• rs2230808
• NM_005502.4:c.4760A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005502.4(ABCA1):​c.4760A>G​(p.Lys1587Arg) variant causes a missense change. The variant allele was found at a frequency of 0.725 in 1,612,774 control chromosomes in the GnomAD database, including 437,586 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. K1587Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.60 (32188 hom., cov: 32)
  • Exomes 𝑓: 0.74 (405398 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 5.95
• Publications: 145 publications found

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 Gene-Disease associations (from GenCC):

• hypoalphalipoproteinemia, primary, 1

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Tangier disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• apolipoprotein A-I deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7720122E-6).
• BP6: Variant 9-104800523-T-C is Benign according to our data. Variant chr9-104800523-T-C is described in ClinVar as Benign. ClinVar VariationId is 364398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005502.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.4760A>G	p.Lys1587Arg	missense	Exon 35 of 50	NP_005493.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.4760A>G	p.Lys1587Arg	missense	Exon 35 of 50	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.4766A>G	p.Lys1589Arg	missense	Exon 35 of 50	ENSP00000504612.1

Frequencies

GnomAD3 genomes AF: 0.604 AC: 91783 AN: 151968 Hom.: 32186 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.765

Gnomad AMR AF: 0.725

Gnomad ASJ AF: 0.746

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.845

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.628

GnomAD2 exomes AF: 0.707 AC: 177856 AN: 251394 AF XY: 0.710

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.790

Gnomad ASJ exome AF: 0.744

Gnomad EAS exome AF: 0.591

Gnomad FIN exome AF: 0.843

Gnomad NFE exome AF: 0.760

Gnomad OTH exome AF: 0.726

GnomAD4 exome AF: 0.738 AC: 1078212 AN: 1460688 Hom.: 405398 Cov.: 41 AF XY: 0.737 AC XY: 535261 AN XY: 726734

African (AFR) AF: 0.195 AC: 6538 AN: 33472

American (AMR) AF: 0.784 AC: 35041 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.748 AC: 19545 AN: 26134

East Asian (EAS) AF: 0.611 AC: 24237 AN: 39684

South Asian (SAS) AF: 0.640 AC: 55189 AN: 86242

European-Finnish (FIN) AF: 0.837 AC: 44706 AN: 53400

Middle Eastern (MID) AF: 0.608 AC: 3503 AN: 5766

European-Non Finnish (NFE) AF: 0.763 AC: 847126 AN: 1110922

Other (OTH) AF: 0.701 AC: 42327 AN: 60348

GnomAD4 genome AF: 0.604 AC: 91810 AN: 152086 Hom.: 32188 Cov.: 32 AF XY: 0.612 AC XY: 45483 AN XY: 74354

African (AFR) AF: 0.220 AC: 9106 AN: 41476

American (AMR) AF: 0.725 AC: 11068 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.746 AC: 2590 AN: 3470

East Asian (EAS) AF: 0.601 AC: 3112 AN: 5174

South Asian (SAS) AF: 0.641 AC: 3086 AN: 4812

European-Finnish (FIN) AF: 0.845 AC: 8950 AN: 10590

Middle Eastern (MID) AF: 0.551 AC: 161 AN: 292

European-Non Finnish (NFE) AF: 0.761 AC: 51716 AN: 67986

Other (OTH) AF: 0.629 AC: 1325 AN: 2108

Alfa AF: 0.705 Hom.: 177521

Bravo AF: 0.580

TwinsUK AF: 0.764 AC: 2834

ALSPAC AF: 0.773 AC: 2981

ESP6500AA AF: 0.243 AC: 1069

ESP6500EA AF: 0.760 AC: 6540

ExAC AF: 0.693 AC: 84189

Asia WGS AF: 0.581 AC: 2025 AN: 3478

EpiCase AF: 0.750

EpiControl AF: 0.750

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29083407, 28008009, 15520867, 20346718, 22929031)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Tangier disease Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Dec 11, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.22
Eigen_PC	Benign	0.045
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0000018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		6.0
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.36
Sift	Benign	1.0	T
Sift4G	Benign	0.80	T
Polyphen		0.018	B
Vest4		0.22
MPC		0.34
ClinPred		0.013	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.46
Mutation Taster		=70/30	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs2230808; hg19: chr9-107562804; COSMIC: COSV66071408;