NM_005502.4:c.421+240G>A

Variant names:

• chr9-104882799-C-T
• rs2275542
• NM_005502.4:c.421+240G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005502.4(ABCA1):​c.421+240G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 152,114 control chromosomes in the GnomAD database, including 6,476 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.29 (6476 hom., cov: 33)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.475
• Publications: 18 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-104882799-C-T is Benign according to our data. Variant chr9-104882799-C-T is described in ClinVar as Benign. ClinVar VariationId is 1248574.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.421+240G>A		intron_variant	Intron 5 of 49	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.421+240G>A		intron_variant	Intron 5 of 49	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.421+240G>A		intron_variant	Intron 5 of 49			ENSP00000504612.1
ABCA1	ENST00000423487.6	c.421+240G>A		intron_variant	Intron 5 of 7	2		ENSP00000416623.2
ABCA1	ENST00000374733.1	c.241+240G>A		intron_variant	Intron 4 of 4	2		ENSP00000363865.1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43656 AN: 151996 Hom.: 6471 Cov.: 33

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.310

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.287 AC: 43683 AN: 152114 Hom.: 6476 Cov.: 33 AF XY: 0.286 AC XY: 21270 AN XY: 74360

African (AFR) AF: 0.236 AC: 9790 AN: 41488

American (AMR) AF: 0.276 AC: 4219 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 998 AN: 3472

East Asian (EAS) AF: 0.315 AC: 1624 AN: 5162

South Asian (SAS) AF: 0.422 AC: 2037 AN: 4824

European-Finnish (FIN) AF: 0.228 AC: 2410 AN: 10586

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21400 AN: 67972

Other (OTH) AF: 0.316 AC: 668 AN: 2114

Alfa AF: 0.308 Hom.: 12921

Bravo AF: 0.287

Asia WGS AF: 0.398 AC: 1380 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.54
DANN	Benign	0.45
PhyloP100		-0.47
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: rs2275542; hg19: chr9-107645080; COSMIC: COSV66058017;