9-104884796-G-A

Variant names:

• chr9-104884796-G-A
• rs4149270
• NM_005502.4:c.161-228C>T

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.161-228C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 152,066 control chromosomes in the GnomAD database, including 7,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.30 (7127 hom., cov: 32)
• Consequence: ABCA1 NM_005502.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.234
• Publications: 11 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=-0.83).
• BP6: Variant 9-104884796-G-A is Benign according to our data. Variant chr9-104884796-G-A is described in ClinVar as Benign. ClinVar VariationId is 1285942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.161-228C>T		intron_variant	Intron 3 of 49	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.161-228C>T		intron_variant	Intron 3 of 49	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.161-228C>T		intron_variant	Intron 3 of 49			ENSP00000504612.1
ABCA1	ENST00000423487.6	c.161-228C>T		intron_variant	Intron 3 of 7	2		ENSP00000416623.2
ABCA1	ENST00000374733.1	c.-20-228C>T		intron_variant	Intron 2 of 4	2		ENSP00000363865.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45440 AN: 151948 Hom.: 7123 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.317

Gnomad EAS AF: 0.316

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.329

Gnomad OTH AF: 0.322

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

GnomAD4 genome AF: 0.299 AC: 45467 AN: 152066 Hom.: 7127 Cov.: 32 AF XY: 0.298 AC XY: 22173 AN XY: 74324

African (AFR) AF: 0.239 AC: 9921 AN: 41468

American (AMR) AF: 0.283 AC: 4318 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 1100 AN: 3470

East Asian (EAS) AF: 0.316 AC: 1635 AN: 5170

South Asian (SAS) AF: 0.510 AC: 2459 AN: 4826

European-Finnish (FIN) AF: 0.229 AC: 2421 AN: 10562

Middle Eastern (MID) AF: 0.401 AC: 117 AN: 292

European-Non Finnish (NFE) AF: 0.329 AC: 22374 AN: 67988

Other (OTH) AF: 0.328 AC: 692 AN: 2108

Alfa AF: 0.310 Hom.: 6231

Bravo AF: 0.297

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.63
PhyloP100		-0.23
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: rs4149270; hg19: chr9-107647077; COSMIC: COSV66058034;