9-104798503-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BP6

The NM_005502.4(ABCA1):c.5039G>A(p.Arg1680Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 0 hom. )

Consequence

ABCA1
NM_005502.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 7.86

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

BP6

Variant 9-104798503-C-T is Benign according to our data. Variant chr9-104798503-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 364394.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4 link	c.5039G>A	p.Arg1680Gln	missense_variant	Exon 37 of 50	ENST00000374736.8	NP_005493.2	O95477B7XCW9B2RUU2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8 link	c.5039G>A	p.Arg1680Gln	missense_variant	Exon 37 of 50	1	NM_005502.4	ENSP00000363868.3		O95477
ABCA1	ENST00000678995.1 link	c.5045G>A	p.Arg1682Gln	missense_variant	Exon 37 of 50			ENSP00000504612.1		A0A7I2V5U0

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000515

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000326

AC:

AN:

251314

Hom.:

AF XY:

0.000339

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000554

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000540

AC:

790

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

372

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.000632

Gnomad4 OTH exome

AF:

0.000844

GnomAD4 genome

AF:

0.000302

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000428

Hom.:

Bravo

AF:

0.000314

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000371

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2025	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 18, 2024

Variant summary: ABCA1 c.5039G>A (p.Arg1680Gln) results in a conservative amino acid change located in the ABC-2 type transporter, transmembrane domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00034 in 266804 control chromosomes, predominantly at a frequency of 0.00055 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 55 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA1 causing Familial Hypoalphalipoproteinemia phenotype (1e-05). c.5039G>A has been reported in the literature in individuals with both high and low level of HDL-C, all without strong evidence for causality (e.g.Cohen_2004, Berge_2010, Sadananda_2015, Peloso_2016, Abdel-Razek_2018, Dong_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypoalphalipoproteinemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15297675, 24497850, 26350511, 26255038, 29150341, 35460704, 20800056). ClinVar contains an entry for this variant (Variation ID: 364394). 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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.81

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.3

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.4

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.97

MVP

0.96

MPC

1.2

ClinPred

0.35

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over