9-104902020-C-T

Variant names:

• chr9-104902020-C-T
• rs1883025
• NM_005502.4:c.66+1594G>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.66+1594G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 151,886 control chromosomes in the GnomAD database, including 5,909 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 0.28 (5909 hom., cov: 32)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215
• Publications: 211 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.356 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.66+1594G>A		intron_variant	Intron 2 of 49	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.66+1594G>A		intron_variant	Intron 2 of 49	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.66+1594G>A		intron_variant	Intron 2 of 49			ENSP00000504612.1
ABCA1	ENST00000423487.6	c.66+1594G>A		intron_variant	Intron 2 of 7	2		ENSP00000416623.2
ABCA1	ENST00000374733.1	c.-114-12825G>A		intron_variant	Intron 1 of 4	2		ENSP00000363865.1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42004 AN: 151770 Hom.: 5896 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.272

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.241

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.283

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

GnomAD4 genome AF: 0.277 AC: 42047 AN: 151886 Hom.: 5909 Cov.: 32 AF XY: 0.273 AC XY: 20297 AN XY: 74274

African (AFR) AF: 0.333 AC: 13781 AN: 41362

American (AMR) AF: 0.277 AC: 4232 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 846 AN: 3472

East Asian (EAS) AF: 0.241 AC: 1247 AN: 5166

South Asian (SAS) AF: 0.371 AC: 1787 AN: 4820

European-Finnish (FIN) AF: 0.182 AC: 1914 AN: 10528

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.254 AC: 17293 AN: 67968

Other (OTH) AF: 0.287 AC: 605 AN: 2110

Alfa AF: 0.267 Hom.: 23940

Bravo AF: 0.286

Asia WGS AF: 0.329 AC: 1144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.5
DANN	Benign	0.39
PhyloP100		-0.21
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: rs1883025; hg19: chr9-107664301; COSMIC: COSV66058145;