9-104826496-C-T

Variant names:

• chr9-104826496-C-T
• rs4149311
• NM_005502.4:c.2337+452G>A

Variant summary

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

The NM_005502.4(ABCA1):​c.2337+452G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 152,170 control chromosomes in the GnomAD database, including 6,214 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 0.24 (6214 hom., cov: 33)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.558
• Publications: 27 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.669 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.2337+452G>A		intron	N/A	NP_005493.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.2337+452G>A		intron	N/A	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.2337+452G>A		intron	N/A	ENSP00000504612.1
	ABCA1	ENST00000494467.1	TSL:3	n.510+452G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35821 AN: 152052 Hom.: 6196 Cov.: 33

Gnomad AFR AF: 0.433

Gnomad AMI AF: 0.0921

Gnomad AMR AF: 0.204

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.223

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

GnomAD4 genome AF: 0.236 AC: 35899 AN: 152170 Hom.: 6214 Cov.: 33 AF XY: 0.236 AC XY: 17536 AN XY: 74414

African (AFR) AF: 0.433 AC: 17975 AN: 41482

American (AMR) AF: 0.205 AC: 3129 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 568 AN: 3470

East Asian (EAS) AF: 0.688 AC: 3556 AN: 5168

South Asian (SAS) AF: 0.158 AC: 765 AN: 4830

European-Finnish (FIN) AF: 0.103 AC: 1090 AN: 10610

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8200 AN: 67992

Other (OTH) AF: 0.227 AC: 480 AN: 2116

Alfa AF: 0.193 Hom.: 4272

Bravo AF: 0.259

Asia WGS AF: 0.395 AC: 1374 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.34
DANN	Benign	0.43
PhyloP100		-0.56
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: rs4149311; hg19: chr9-107588777;