9-104858586-C-T

Variant names:

• chr9-104858586-C-T
• rs2230806
• NM_005502.4:c.656G>A

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.656G>A​(p.Arg219Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,856 control chromosomes in the GnomAD database, including 80,178 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R219R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.38 (13060 hom., cov: 33)
  • Exomes 𝑓: 0.29 (67118 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.545
• Publications: 283 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=1.2091895E-5).
• BP6: Variant 9-104858586-C-T is Benign according to our data. Variant chr9-104858586-C-T is described in ClinVar as Benign. ClinVar VariationId is 9506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.619 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.656G>A	p.Arg219Lys	missense	Exon 7 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.656G>A	p.Arg219Lys	missense	Exon 7 of 50	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.656G>A	p.Arg219Lys	missense	Exon 7 of 50	ENSP00000504612.1
	ABCA1	ENST00000423487.6	TSL:2	c.656G>A	p.Arg219Lys	missense	Exon 7 of 8	ENSP00000416623.2

Frequencies

GnomAD3 genomes AF: 0.384 AC: 58319 AN: 151970 Hom.: 13020 Cov.: 33

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.377

GnomAD2 exomes AF: 0.324 AC: 81377 AN: 251448 AF XY: 0.320

Gnomad AFR exome AF: 0.630

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.293 AC: 428401 AN: 1461766 Hom.: 67118 Cov.: 42 AF XY: 0.295 AC XY: 214422 AN XY: 727200

African (AFR) AF: 0.647 AC: 21668 AN: 33476

American (AMR) AF: 0.328 AC: 14667 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 7337 AN: 26136

East Asian (EAS) AF: 0.472 AC: 18746 AN: 39698

South Asian (SAS) AF: 0.368 AC: 31746 AN: 86256

European-Finnish (FIN) AF: 0.220 AC: 11768 AN: 53412

Middle Eastern (MID) AF: 0.404 AC: 2331 AN: 5766

European-Non Finnish (NFE) AF: 0.271 AC: 300877 AN: 1111908

Other (OTH) AF: 0.319 AC: 19261 AN: 60390

GnomAD4 genome AF: 0.384 AC: 58426 AN: 152090 Hom.: 13060 Cov.: 33 AF XY: 0.382 AC XY: 28416 AN XY: 74352

African (AFR) AF: 0.626 AC: 25941 AN: 41464

American (AMR) AF: 0.346 AC: 5288 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 959 AN: 3470

East Asian (EAS) AF: 0.427 AC: 2208 AN: 5176

South Asian (SAS) AF: 0.372 AC: 1796 AN: 4822

European-Finnish (FIN) AF: 0.222 AC: 2347 AN: 10580

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18555 AN: 67986

Other (OTH) AF: 0.382 AC: 808 AN: 2116

Alfa AF: 0.315 Hom.: 34779

Bravo AF: 0.404

TwinsUK AF: 0.259 AC: 959

ALSPAC AF: 0.268 AC: 1032

ESP6500AA AF: 0.606 AC: 2672

ESP6500EA AF: 0.281 AC: 2420

ExAC AF: 0.330 AC: 40042

Asia WGS AF: 0.423 AC: 1471 AN: 3478

EpiCase AF: 0.288

EpiControl AF: 0.283

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Tangier disease (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypoalphalipoproteinemia, primary, 1 (1)
-	-	1	RECLASSIFIED - ABCA1 POLYMORPHISM (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	6.2
DANN	Benign	0.83
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.11	N
PhyloP100		0.55
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.19
Sift	Benign	0.62	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.041
MPC		0.18
ClinPred		0.00098	T
GERP RS		0.057
Varity_R		0.10
gMVP		0.089
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2230806; hg19: chr9-107620867; COSMIC: COSV66057914; COSMIC: COSV66057914;