9-104928254-G-C

Variant names:

• chr9-104928254-G-C
• rs2740483
• ENST00000435915.1:n.358+344G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000435915.1(ENSG00000226334):​n.358+344G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.752 in 152,310 control chromosomes in the GnomAD database, including 43,358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43305 hom., cov: 33)
  • Exomes 𝑓: 0.71 (53 hom.)
• Consequence: ENSG00000226334 ENST00000435915.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.426
• Publications: 21 publications found

Genes affected

ENSG00000226334 (HGNC:):

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=-0.8).
• BP6: Variant 9-104928254-G-C is Benign according to our data. Variant chr9-104928254-G-C is described in ClinVar as Benign. ClinVar VariationId is 369619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000435915.1. 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
	LOC105376196	NR_188620.1		n.1122+344G>C		intron	N/A
	ABCA1	NM_005502.4	MANE Select	c.-412C>G		upstream_gene	N/A	NP_005493.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000226334	ENST00000435915.1	TSL:3	n.358+344G>C		intron	N/A
	ENSG00000226334	ENST00000820514.1		n.1164+344G>C		intron	N/A
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.-412C>G		upstream_gene	N/A	ENSP00000363868.3

Frequencies

GnomAD3 genomes AF: 0.752 AC: 114251 AN: 151986 Hom.: 43268 Cov.: 33

Gnomad AFR AF: 0.833

Gnomad AMI AF: 0.701

Gnomad AMR AF: 0.764

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.798

Gnomad SAS AF: 0.802

Gnomad FIN AF: 0.738

Gnomad MID AF: 0.822

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.747

GnomAD4 exome AF: 0.714 AC: 147 AN: 206 Hom.: 53 Cov.: 0 AF XY: 0.743 AC XY: 110 AN XY: 148

African (AFR) AF: 0.625 AC: 5 AN: 8

American (AMR) AF: 1.00 AC: 2 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.750 AC: 3 AN: 4

South Asian (SAS) AF: 0.833 AC: 5 AN: 6

European-Finnish (FIN) AF: 0.750 AC: 15 AN: 20

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.697 AC: 106 AN: 152

Other (OTH) AF: 0.750 AC: 9 AN: 12

GnomAD4 genome AF: 0.752 AC: 114341 AN: 152104 Hom.: 43305 Cov.: 33 AF XY: 0.755 AC XY: 56137 AN XY: 74338

African (AFR) AF: 0.833 AC: 34589 AN: 41506

American (AMR) AF: 0.765 AC: 11695 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2834 AN: 3468

East Asian (EAS) AF: 0.797 AC: 4100 AN: 5142

South Asian (SAS) AF: 0.802 AC: 3864 AN: 4818

European-Finnish (FIN) AF: 0.738 AC: 7795 AN: 10568

Middle Eastern (MID) AF: 0.832 AC: 243 AN: 292

European-Non Finnish (NFE) AF: 0.691 AC: 47012 AN: 67996

Other (OTH) AF: 0.743 AC: 1570 AN: 2112

Alfa AF: 0.693 Hom.: 18190

Bravo AF: 0.757

Asia WGS AF: 0.789 AC: 2745 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

May 08, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 11940086)

Familial High Density Lipoprotein Deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tangier disease Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.62
PhyloP100		-0.43
PromoterAI		0.0042	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2740483; hg19: chr9-107690535;