NM_005502.4:c.4593-26G>C

Variant names:

• chr9-104802185-C-G
• rs2297404
• NM_005502.4:c.4593-26G>C

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.4593-26G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0788 in 1,595,932 control chromosomes in the GnomAD database, including 5,786 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (431 hom., cov: 33)
  • Exomes 𝑓: 0.080 (5355 hom.)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.157
• Publications: 17 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=-0.61).
• BP6: Variant 9-104802185-C-G is Benign according to our data. Variant chr9-104802185-C-G is described in ClinVar as Benign. ClinVar VariationId is 1297172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.4593-26G>C		intron_variant	Intron 33 of 49	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.4593-26G>C		intron_variant	Intron 33 of 49	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.4599-26G>C		intron_variant	Intron 33 of 49			ENSP00000504612.1

Frequencies

GnomAD3 genomes AF: 0.0666 AC: 10122 AN: 152084 Hom.: 429 Cov.: 33

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0552

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.0987

Gnomad FIN AF: 0.0445

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0749

Gnomad OTH AF: 0.0731

GnomAD2 exomes AF: 0.0785 AC: 19691 AN: 250934 AF XY: 0.0813

Gnomad AFR exome AF: 0.0408

Gnomad AMR exome AF: 0.0356

Gnomad ASJ exome AF: 0.0379

Gnomad EAS exome AF: 0.234

Gnomad FIN exome AF: 0.0462

Gnomad NFE exome AF: 0.0759

Gnomad OTH exome AF: 0.0673

GnomAD4 exome AF: 0.0801 AC: 115648 AN: 1443730 Hom.: 5355 Cov.: 28 AF XY: 0.0808 AC XY: 58160 AN XY: 719680

African (AFR) AF: 0.0399 AC: 1319 AN: 33024

American (AMR) AF: 0.0360 AC: 1608 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0387 AC: 1007 AN: 26016

East Asian (EAS) AF: 0.212 AC: 8393 AN: 39608

South Asian (SAS) AF: 0.0994 AC: 8537 AN: 85880

European-Finnish (FIN) AF: 0.0474 AC: 2533 AN: 53400

Middle Eastern (MID) AF: 0.0829 AC: 475 AN: 5728

European-Non Finnish (NFE) AF: 0.0793 AC: 86922 AN: 1095554

Other (OTH) AF: 0.0811 AC: 4854 AN: 59818

GnomAD4 genome AF: 0.0666 AC: 10131 AN: 152202 Hom.: 431 Cov.: 33 AF XY: 0.0652 AC XY: 4853 AN XY: 74420

African (AFR) AF: 0.0393 AC: 1634 AN: 41538

American (AMR) AF: 0.0551 AC: 842 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 140 AN: 3468

East Asian (EAS) AF: 0.228 AC: 1180 AN: 5176

South Asian (SAS) AF: 0.0996 AC: 480 AN: 4820

European-Finnish (FIN) AF: 0.0445 AC: 472 AN: 10596

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0750 AC: 5097 AN: 68004

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.0422 Hom.: 45

Bravo AF: 0.0659

Asia WGS AF: 0.158 AC: 547 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17510949) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.70
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2297404; hg19: chr9-107564466; COSMIC: COSV66072242;