rs187652566

Variant names:

• chr9-104822664-C-A
• rs187652566
• NM_005502.4:c.2660G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BS1 BS2_Supporting

The NM_005502.4(ABCA1):​c.2660G>T​(p.Cys887Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000398 in 1,614,030 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (2 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 6.17

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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019330889).
• BP6: Variant 9-104822664-C-A is Benign according to our data. Variant chr9-104822664-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225290.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1, Benign=3}.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000407 (62/152272) while in subpopulation EAS AF = 0.00348 (18/5166). AF 95% confidence interval is 0.00225. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.2660G>T	p.Cys887Phe	missense_variant	Exon 19 of 50	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.2660G>T	p.Cys887Phe	missense_variant	Exon 19 of 50	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.2660G>T	p.Cys887Phe	missense_variant	Exon 19 of 50			ENSP00000504612.1

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00348

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000461 AC: 116 AN: 251376 AF XY: 0.000449

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00174

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.000360

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000397 AC: 580 AN: 1461758 Hom.: 2 Cov.: 31 AF XY: 0.000369 AC XY: 268 AN XY: 727186

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33472

Gnomad4 AMR exome AF: 0.0000447 AC: 2 AN: 44722

Gnomad4 ASJ exome AF: 0.0000765 AC: 2 AN: 26134

Gnomad4 EAS exome AF: 0.00743 AC: 295 AN: 39700

Gnomad4 SAS exome AF: 0.000336 AC: 29 AN: 86254

Gnomad4 FIN exome AF: 0.00129 AC: 69 AN: 53340

Gnomad4 NFE exome AF: 0.000138 AC: 153 AN: 1111988

Gnomad4 Remaining exome AF: 0.000480 AC: 29 AN: 60388

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74448

Gnomad4 AFR AF: 0.0000722 AC: 0.0000721917 AN: 0.0000721917

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00348 AC: 0.00348432 AN: 0.00348432

Gnomad4 SAS AF: 0.000829 AC: 0.000828844 AN: 0.000828844

Gnomad4 FIN AF: 0.00160 AC: 0.00160105 AN: 0.00160105

Gnomad4 NFE AF: 0.000294 AC: 0.000294023 AN: 0.000294023

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000310 Hom.: 1

Bravo AF: 0.000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000585 AC: 71

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has been reported in individuals with increased HDL-cholesterol and decreased total cholesterol levels (Hu et al., 2009; Service et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20800056, 24497850, 19743957, 32041611) -

Hypercholesterolemia, familial, 1 Uncertain:1

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Cardiovascular phenotype Benign:1

Feb 21, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Hypoalphalipoproteinemia, primary, 1 Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Benign	0.87
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.050
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.65	N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.49	N
REVEL	Uncertain	0.49
Sift	Benign	0.52	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.63
MVP		0.87
MPC		1.6
ClinPred		0.037	T
GERP RS		5.5
Varity_R		0.35
gMVP		0.82
Mutation Taster		=39/61	disease causing

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

Publications

LitVar

Other links and lift over

dbSNP: rs187652566; hg19: chr9-107584945;