chr9-104882006-G-A

Variant names:

• chr9-104882006-G-A
• rs4149271
• NM_005502.4:c.421+1033C>T

Variant summary

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

The NM_005502.4(ABCA1):​c.421+1033C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 118,522 control chromosomes in the GnomAD database, including 3,172 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 (3172 hom., cov: 22)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 8 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.421+1033C>T		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+1033C>T		intron_variant	Intron 5 of 49	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.421+1033C>T		intron_variant	Intron 5 of 49			ENSP00000504612.1
ABCA1	ENST00000423487.6	c.421+1033C>T		intron_variant	Intron 5 of 7	2		ENSP00000416623.2
ABCA1	ENST00000374733.1	c.241+1033C>T		intron_variant	Intron 4 of 4	2		ENSP00000363865.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 28890 AN: 118458 Hom.: 3178 Cov.: 22

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.429

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.322

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.249

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

GnomAD4 genome AF: 0.244 AC: 28902 AN: 118522 Hom.: 3172 Cov.: 22 AF XY: 0.253 AC XY: 14043 AN XY: 55422

African (AFR) AF: 0.203 AC: 6371 AN: 31428

American (AMR) AF: 0.289 AC: 2686 AN: 9304

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 789 AN: 3098

East Asian (EAS) AF: 0.323 AC: 1189 AN: 3682

South Asian (SAS) AF: 0.428 AC: 1574 AN: 3676

European-Finnish (FIN) AF: 0.258 AC: 1405 AN: 5442

Middle Eastern (MID) AF: 0.323 AC: 53 AN: 164

European-Non Finnish (NFE) AF: 0.239 AC: 14163 AN: 59330

Other (OTH) AF: 0.253 AC: 404 AN: 1598

Alfa AF: 0.206 Hom.: 5809

Bravo AF: 0.201

Asia WGS AF: 0.314 AC: 1088 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	10
DANN	Benign	0.67
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4149271; hg19: chr9-107644287; COSMIC: COSV66058011;