9-104800523-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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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

Sel.	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

Sel.	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	O95477
	ABCA1	ENST00000678995.1		c.4766A>G	p.Lys1589Arg	missense	Exon 35 of 50	ENSP00000504612.1	A0A7I2V5U0

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	2	Tangier disease (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypoalphalipoproteinemia, primary, 1 (1)

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;