rs145183203

chr9-104884475-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3 BP4_Strong BP6

The NM_005502.4(ABCA1):c.254C>T(p.Pro85Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,202 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P85S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 10.0

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

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.013464153).
• BP6: Variant 9-104884475-G-A is Benign according to our data. Variant chr9-104884475-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 364464.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA1	NM_005502.4	c.254C>T	p.Pro85Leu	missense_variant	4/50	ENST00000374736.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA1	ENST00000374736.8	c.254C>T	p.Pro85Leu	missense_variant	4/50	1	NM_005502.4	P1
ABCA1	ENST00000678995.1	c.254C>T	p.Pro85Leu	missense_variant	4/50
ABCA1	ENST00000423487.6	c.254C>T	p.Pro85Leu	missense_variant	4/8	2
ABCA1	ENST00000374733.1	c.74C>T	p.Pro25Leu	missense_variant	3/5	2

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00536

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00143 AC: 359 AN: 251460 Hom.: 1 AF XY: 0.00144 AC XY: 196 AN XY: 135904

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00144

Gnomad FIN exome AF: 0.00508

Gnomad NFE exome AF: 0.00149

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00135 AC: 1969 AN: 1461872 Hom.: 3 Cov.: 31 AF XY: 0.00138 AC XY: 1006 AN XY: 727236

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.00485

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.00136 AC XY: 101 AN XY: 74500

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00536

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.000733

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 24, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 01, 2022

Variant summary: ABCA1 c.254C>T (p.Pro85Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 258052 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 112.84 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA1 causing Early Onset Coronary Artery Disease phenotype (1.3e-05), strongly suggesting that the variant is benign. The variant has been reported in the literature in the heterozygous state only (or unstated), in individuals with low HDL-C, FH, MI and hypoalphalipoproteinemia (Colin_2014, Beaudoin_2012, Luirink_2019, Geller_2018, Dong_2022), and in some tested individuals was associated with lower HDL-C levels (Cohen_2004), without strong evidence for causality. The variant was found in at least 1 pt with critically low HDL and personal history of CAD, however 4 additional family members who carried this variant heterozygously presented only with hypoalphalipoproteinemia but were cardiologically normal (Hong et al.,2002). In at least 1 large scale genome sequencing project, the variant was not associated with HDL-C levels (Morrison_2013) and was reported as 'polymorphism' by Kiss et. al, 2007. These reports do not provide unequivocal conclusions about association of the variant with Early Onset Coronary Artery Disease. In addition, cholesterol efflux was found to be higher in cells from an individual with the variant compared to normal controls, while other variants associated with lower HDL-C levels had cholesterol efflux levels less than two standard deviations below the mean in subjects with normal HDL-C (Cohen_2004). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Two submitters have classified the variant as likely benign, while two classified as VUS and one classified as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. -

Hypoalphalipoproteinemia, primary, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Tangier disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;T;D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;T;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.013	T;T;T
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.84
Sift	Benign	0.71	T;T;D
Sift4G	Benign	0.24	T;T;D
Polyphen		0.97	D;.;D
Vest4		0.59
MVP		0.99
MPC		0.49
ClinPred		0.062	T
GERP RS		5.4
Varity_R		0.52
gMVP		0.74

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: rs145183203; hg19: chr9-107646756; COSMIC: COSV66059807;