rs536009

Positions:

• chr17-69277741-C-A
• chr17-69277741-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172232.4(ABCA5):​c.2494G>T​(p.Ala832Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 1,607,574 control chromosomes in the GnomAD database, including 581,032 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.79 (48729 hom., cov: 31)
  • Exomes 𝑓: 0.85 (532303 hom.)
• Consequence: ABCA5 NM_172232.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.321

Genes affected

ABCA5 (HGNC:35): (ATP binding cassette subfamily A member 5) 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, and White). This encoded protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This gene is clustered among 4 other ABC1 family members on 17q24, but neither the substrate nor the function of this gene is known. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1026686E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA5	NM_172232.4	c.2494G>T	p.Ala832Ser	missense_variant	19/39	ENST00000392676.8
ABCA5	NM_018672.5	c.2494G>T	p.Ala832Ser	missense_variant	18/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA5	ENST00000392676.8	c.2494G>T	p.Ala832Ser	missense_variant	19/39	1	NM_172232.4	P1

Frequencies

GnomAD3 genomes AF: 0.793 AC: 120528 AN: 151936 Hom.: 48698 Cov.: 31

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.954

Gnomad AMR AF: 0.797

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.945

Gnomad SAS AF: 0.909

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.796

GnomAD3 exomes AF: 0.848 AC: 207685 AN: 244946 Hom.: 88729 AF XY: 0.855 AC XY: 113208 AN XY: 132346

Gnomad AFR exome AF: 0.629

Gnomad AMR exome AF: 0.801

Gnomad ASJ exome AF: 0.867

Gnomad EAS exome AF: 0.946

Gnomad SAS exome AF: 0.900

Gnomad FIN exome AF: 0.857

Gnomad NFE exome AF: 0.860

Gnomad OTH exome AF: 0.851

GnomAD4 exome AF: 0.854 AC: 1242822 AN: 1455520 Hom.: 532303 Cov.: 42 AF XY: 0.857 AC XY: 620151 AN XY: 723760

Gnomad4 AFR exome AF: 0.623

Gnomad4 AMR exome AF: 0.795

Gnomad4 ASJ exome AF: 0.867

Gnomad4 EAS exome AF: 0.955

Gnomad4 SAS exome AF: 0.901

Gnomad4 FIN exome AF: 0.853

Gnomad4 NFE exome AF: 0.856

Gnomad4 OTH exome AF: 0.847

GnomAD4 genome AF: 0.793 AC: 120606 AN: 152054 Hom.: 48729 Cov.: 31 AF XY: 0.797 AC XY: 59215 AN XY: 74330

Gnomad4 AFR AF: 0.629

Gnomad4 AMR AF: 0.796

Gnomad4 ASJ AF: 0.855

Gnomad4 EAS AF: 0.945

Gnomad4 SAS AF: 0.910

Gnomad4 FIN AF: 0.857

Gnomad4 NFE AF: 0.857

Gnomad4 OTH AF: 0.797

Alfa AF: 0.849 Hom.: 120426

Bravo AF: 0.778

TwinsUK AF: 0.855 AC: 3169

ALSPAC AF: 0.859 AC: 3309

ESP6500AA AF: 0.629 AC: 2769

ESP6500EA AF: 0.855 AC: 7348

ExAC AF: 0.847 AC: 102827

Asia WGS AF: 0.890 AC: 3088 AN: 3472

EpiCase AF: 0.863

EpiControl AF: 0.862

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.54
DEOGEN2	Benign	0.048	T;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.014	N
MetaRNN	Benign	0.0000011	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.040	N;.;.
REVEL	Benign	0.13
Sift	Benign	1.0	T;.;.
Sift4G	Benign	0.77	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.012
MPC		0.047
ClinPred		0.0011	T
GERP RS		2.1
Varity_R		0.025
gMVP		0.071

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: rs536009; hg19: chr17-67273882;