chr9-137028748-C-T

Variant names:

• chr9-137028748-C-T
• rs374868755
• ENST00000459850.5:n.168G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_212533.3(ABCA2):​c.125G>A​(p.Arg42Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,279,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ABCA2 NM_212533.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.19
• 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_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.033659548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA2	NM_212533.3	c.125G>A	p.Arg42Gln	missense_variant	Exon 1 of 49		NP_997698.1
ABCA2	XM_047422921.1	c.125G>A	p.Arg42Gln	missense_variant	Exon 1 of 48		XP_047278877.1
LINC02908	NR_171031.1	n.448+837C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA2	ENST00000459850.5	n.168G>A		non_coding_transcript_exon_variant	Exon 1 of 47	1
ABCA2	ENST00000487109.5	n.125G>A		non_coding_transcript_exon_variant	Exon 1 of 47	1		ENSP00000418662.1
ABCA2	ENST00000614293.5	c.125G>A	p.Arg42Gln	missense_variant	Exon 1 of 49	5		ENSP00000481105.2

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000248 AC: 4 AN: 161222 AF XY: 0.00

Gnomad AFR exome AF: 0.000428

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000887 AC: 10 AN: 1127030 Hom.: 0 Cov.: 29 AF XY: 0.00000360 AC XY: 2 AN XY: 555596

African (AFR) AF: 0.000345 AC: 7 AN: 20318

American (AMR) AF: 0.00 AC: 0 AN: 17384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13698

East Asian (EAS) AF: 0.00 AC: 0 AN: 10530

South Asian (SAS) AF: 0.00 AC: 0 AN: 70078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4156

European-Non Finnish (NFE) AF: 0.00000217 AC: 2 AN: 920502

Other (OTH) AF: 0.0000249 AC: 1 AN: 40194

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74346

African (AFR) AF: 0.000169 AC: 7 AN: 41452

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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: 0.00 AC: 0 AN: 68016

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

Alfa AF: 0.0000285 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000532 AC: 2

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.125G>A (p.R42Q) alteration is located in exon 1 (coding exon 1) of the ABCA2 gene. This alteration results from a G to A substitution at nucleotide position 125, causing the arginine (R) at amino acid position 42 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.5
DANN	Benign	0.82
DEOGEN2	Benign	0.19	.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.034	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		-3.2
Sift4G	Benign	0.50	T;.
Vest4		0.050
MVP		0.093
ClinPred		0.012	T
GERP RS		-2.2
PromoterAI		-0.044	Neutral
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: rs374868755; hg19: chr9-139923200;