9-104800523-T-G

Variant names:

• chr9-104800523-T-G
• rs2230808
• NM_005502.4:c.4760A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005502.4(ABCA1):​c.4760A>C​(p.Lys1587Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1587R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ABCA1 NM_005502.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.95
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA1	NM_005502.4	c.4760A>C	p.Lys1587Thr	missense_variant	Exon 35 of 50	ENST00000374736.8	NP_005493.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA1	ENST00000374736.8	c.4760A>C	p.Lys1587Thr	missense_variant	Exon 35 of 50	1	NM_005502.4	ENSP00000363868.3
ABCA1	ENST00000678995.1	c.4766A>C	p.Lys1589Thr	missense_variant	Exon 35 of 50			ENSP00000504612.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 41

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	-0.017	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.52
Sift	Benign	0.044	D
Sift4G	Benign	0.42	T
Polyphen		0.11	B
Vest4		0.69
MutPred		0.44		Gain of sheet (P = 0.0085);
MVP		0.94
MPC		0.96
ClinPred		0.90	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.71
Mutation Taster		=46/54	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

Other links and lift over

dbSNP: rs2230808; hg19: chr9-107562804;