rs749054833

Variant names:

• chr9-137028776-AG-A
• rs749054833
• ENST00000459850.5:n.139delC

Your query was ambiguous. Multiple possible variants found:

• chr9-137028776-AG-A
• chr9-137028776-AG-AGG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_212533.3(ABCA2):​c.96delC​(p.Phe33SerfsTer49) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000543 in 1,288,834 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: ABCA2 NM_212533.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.902
• Publications: 0 publications found

Genes affected

ABCA2 (HGNC:32): (ATP binding cassette subfamily A member 2) 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. This protein is highly expressed in brain tissue and may play a role in macrophage lipid metabolism and neural development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

LINC02908 (HGNC:31426): (long intergenic non-protein coding RNA 2908)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA2	NM_212533.3	c.96delC	p.Phe33SerfsTer49	frameshift_variant	Exon 1 of 49		NP_997698.1
ABCA2	XM_047422921.1	c.96delC	p.Phe33SerfsTer49	frameshift_variant	Exon 1 of 48		XP_047278877.1
LINC02908	NR_171031.1	n.448+871delG		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA2	ENST00000459850.5	n.139delC		non_coding_transcript_exon_variant	Exon 1 of 47	1
ABCA2	ENST00000487109.5	n.96delC		non_coding_transcript_exon_variant	Exon 1 of 47	1		ENSP00000418662.1
ABCA2	ENST00000614293.5	c.96delC	p.Phe33SerfsTer49	frameshift_variant	Exon 1 of 49	5		ENSP00000481105.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000116 AC: 2 AN: 172348 AF XY: 0.0000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000589

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000118

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000440 AC: 5 AN: 1136670 Hom.: 0 Cov.: 29 AF XY: 0.00000357 AC XY: 2 AN XY: 560848

African (AFR) AF: 0.0000481 AC: 1 AN: 20786

American (AMR) AF: 0.0000523 AC: 1 AN: 19116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14076

East Asian (EAS) AF: 0.00 AC: 0 AN: 11386

South Asian (SAS) AF: 0.00 AC: 0 AN: 71748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4232

European-Non Finnish (NFE) AF: 0.00000325 AC: 3 AN: 924156

Other (OTH) AF: 0.00 AC: 0 AN: 40628

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 01, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; No data available from control populations to assess the frequency of this variant -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.90
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs749054833; hg19: chr9-139923228;