9-104819468-A-C

Variant names:

• chr9-104819468-A-C
• rs2254884
• NM_005502.4:c.3241+118T>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.3241+118T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 1,418,434 control chromosomes in the GnomAD database, including 63,479 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5371 hom., cov: 32)
  • Exomes 𝑓: 0.30 (58108 hom.)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.279
• Publications: 12 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 (BayesDel_noAF=-0.93).
• BP6: Variant 9-104819468-A-C is Benign according to our data. Variant chr9-104819468-A-C is described in ClinVar as Benign. ClinVar VariationId is 1263599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.531 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.3241+118T>G		intron	N/A	NP_005493.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.3241+118T>G		intron	N/A	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.3241+118T>G		intron	N/A	ENSP00000504612.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37086 AN: 152034 Hom.: 5372 Cov.: 32

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.260

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.285

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.275

GnomAD4 exome AF: 0.297 AC: 376009 AN: 1266282 Hom.: 58108 AF XY: 0.297 AC XY: 189953 AN XY: 639538

African (AFR) AF: 0.0990 AC: 2916 AN: 29456

American (AMR) AF: 0.275 AC: 12155 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 7779 AN: 24890

East Asian (EAS) AF: 0.528 AC: 20400 AN: 38620

South Asian (SAS) AF: 0.266 AC: 21698 AN: 81618

European-Finnish (FIN) AF: 0.236 AC: 11236 AN: 47638

Middle Eastern (MID) AF: 0.276 AC: 1052 AN: 3812

European-Non Finnish (NFE) AF: 0.300 AC: 282868 AN: 942314

Other (OTH) AF: 0.296 AC: 15905 AN: 53720

GnomAD4 genome AF: 0.244 AC: 37092 AN: 152152 Hom.: 5371 Cov.: 32 AF XY: 0.243 AC XY: 18074 AN XY: 74398

African (AFR) AF: 0.105 AC: 4353 AN: 41536

American (AMR) AF: 0.260 AC: 3979 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1096 AN: 3472

East Asian (EAS) AF: 0.548 AC: 2827 AN: 5158

South Asian (SAS) AF: 0.267 AC: 1286 AN: 4822

European-Finnish (FIN) AF: 0.240 AC: 2541 AN: 10592

Middle Eastern (MID) AF: 0.282 AC: 83 AN: 294

European-Non Finnish (NFE) AF: 0.294 AC: 20013 AN: 67956

Other (OTH) AF: 0.277 AC: 585 AN: 2114

Alfa AF: 0.280 Hom.: 9702

Bravo AF: 0.242

Asia WGS AF: 0.383 AC: 1334 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.5
DANN	Benign	0.64
PhyloP100		0.28
Mutation Taster		=100/0	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: rs2254884; hg19: chr9-107581749; COSMIC: COSV66067082;