9-104806424-C-T

Variant names:

• chr9-104806424-C-T
• rs2066716
• NM_005502.4:c.4281G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005502.4(ABCA1):​c.4281G>A​(p.Thr1427Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,613,794 control chromosomes in the GnomAD database, including 8,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1427T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.087 (824 hom., cov: 32)
  • Exomes 𝑓: 0.091 (7824 hom.)
• Consequence: ABCA1 NM_005502.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.190
• Publications: 33 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 9-104806424-C-T is Benign according to our data. Variant chr9-104806424-C-T is described in ClinVar as Benign. ClinVar VariationId is 364402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	NM_005502.4	MANE Select	c.4281G>A	p.Thr1427Thr	synonymous	Exon 31 of 50	NP_005493.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA1	ENST00000374736.8	TSL:1 MANE Select	c.4281G>A	p.Thr1427Thr	synonymous	Exon 31 of 50	ENSP00000363868.3
	ABCA1	ENST00000678995.1		c.4287G>A	p.Thr1429Thr	synonymous	Exon 31 of 50	ENSP00000504612.1

Frequencies

GnomAD3 genomes AF: 0.0870 AC: 13222 AN: 152020 Hom.: 824 Cov.: 32

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.0583

Gnomad FIN AF: 0.0544

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0836

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.114 AC: 28704 AN: 250980 AF XY: 0.108

Gnomad AFR exome AF: 0.0312

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.287

Gnomad FIN exome AF: 0.0565

Gnomad NFE exome AF: 0.0862

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.0911 AC: 133201 AN: 1461656 Hom.: 7824 Cov.: 32 AF XY: 0.0897 AC XY: 65255 AN XY: 727128

African (AFR) AF: 0.0324 AC: 1085 AN: 33480

American (AMR) AF: 0.236 AC: 10547 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3570 AN: 26134

East Asian (EAS) AF: 0.292 AC: 11591 AN: 39694

South Asian (SAS) AF: 0.0557 AC: 4804 AN: 86246

European-Finnish (FIN) AF: 0.0569 AC: 3036 AN: 53380

Middle Eastern (MID) AF: 0.0856 AC: 494 AN: 5768

European-Non Finnish (NFE) AF: 0.0831 AC: 92409 AN: 1111864

Other (OTH) AF: 0.0938 AC: 5665 AN: 60390

GnomAD4 genome AF: 0.0869 AC: 13227 AN: 152138 Hom.: 824 Cov.: 32 AF XY: 0.0887 AC XY: 6599 AN XY: 74382

African (AFR) AF: 0.0352 AC: 1464 AN: 41534

American (AMR) AF: 0.194 AC: 2963 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3470

East Asian (EAS) AF: 0.294 AC: 1511 AN: 5148

South Asian (SAS) AF: 0.0583 AC: 281 AN: 4816

European-Finnish (FIN) AF: 0.0544 AC: 576 AN: 10592

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0836 AC: 5683 AN: 67970

Other (OTH) AF: 0.113 AC: 239 AN: 2110

Alfa AF: 0.0905 Hom.: 2456

Bravo AF: 0.0994

Asia WGS AF: 0.161 AC: 560 AN: 3478

EpiCase AF: 0.0899

EpiControl AF: 0.0915

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Oct 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

Mar 21, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Tangier disease Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Hypoalphalipoproteinemia, primary, 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.4
DANN	Benign	0.41
PhyloP100		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	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: rs2066716; hg19: chr9-107568705; COSMIC: COSV66067270;