9-104915008-A-G

Variant names:

• chr9-104915008-A-G
• rs4149263
• NM_005502.4:c.-92-11237T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005502.4(ABCA1):​c.-92-11237T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 152,176 control chromosomes in the GnomAD database, including 2,651 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2651 hom., cov: 32)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.11
• Publications: 14 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

ENSG00000306712 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.202 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.-92-11237T>C		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.-92-11237T>C		intron	N/A	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.-92-11237T>C		intron	N/A	ENSP00000504612.1
	ABCA1	ENST00000423487.6	TSL:2	c.-92-11237T>C		intron	N/A	ENSP00000416623.2

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27472 AN: 152058 Hom.: 2655 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.207

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

GnomAD4 genome AF: 0.180 AC: 27464 AN: 152176 Hom.: 2651 Cov.: 32 AF XY: 0.181 AC XY: 13474 AN XY: 74412

African (AFR) AF: 0.134 AC: 5573 AN: 41538

American (AMR) AF: 0.158 AC: 2418 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 995 AN: 3470

East Asian (EAS) AF: 0.174 AC: 901 AN: 5172

South Asian (SAS) AF: 0.203 AC: 979 AN: 4826

European-Finnish (FIN) AF: 0.188 AC: 1995 AN: 10590

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13924 AN: 67990

Other (OTH) AF: 0.204 AC: 429 AN: 2108

Alfa AF: 0.200 Hom.: 6023

Bravo AF: 0.176

Asia WGS AF: 0.187 AC: 649 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0080
DANN	Benign	0.36
PhyloP100		-4.1
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: rs4149263; hg19: chr9-107677289; COSMIC: COSV66058172;