rs3764645

Variant names:

• chr19-1042810-A-G
• rs3764645
• NM_019112.4:c.563A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019112.4(ABCA7):​c.563A>G​(p.Glu188Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.473 in 1,608,896 control chromosomes in the GnomAD database, including 184,990 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E188D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.42 (14587 hom., cov: 33)
  • Exomes 𝑓: 0.48 (170403 hom.)
• Consequence: ABCA7 NM_019112.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.58
• Publications: 52 publications found

Genes affected

ABCA7 (HGNC:37): (ATP binding cassette subfamily A member 7) The 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 intra-cellular 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 full transporter has been detected predominantly in myelo-lymphatic tissues with the highest expression in peripheral leukocytes, thymus, spleen, and bone marrow. The function of this protein is not yet known; however, the expression pattern suggests a role in lipid homeostasis in cells of the immune system. [provided by RefSeq, Jul 2008]

ABCA7 Gene-Disease associations (from GenCC):

• Alzheimer disease 9

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.5857913E-6).
• BP6: Variant 19-1042810-A-G is Benign according to our data. Variant chr19-1042810-A-G is described in ClinVar as Benign. ClinVar VariationId is 1237748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019112.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA7	NM_019112.4	MANE Select	c.563A>G	p.Glu188Gly	missense	Exon 7 of 47	NP_061985.2	Q8IZY2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA7	ENST00000263094.11	TSL:5 MANE Select	c.563A>G	p.Glu188Gly	missense	Exon 7 of 47	ENSP00000263094.6	Q8IZY2-1
	ABCA7	ENST00000433129.6	TSL:1	n.1243A>G		non_coding_transcript_exon	Exon 6 of 44
	ABCA7	ENST00000526885.5	TSL:1	n.*66A>G		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63529 AN: 151950 Hom.: 14576 Cov.: 33

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.431

GnomAD2 exomes AF: 0.496 AC: 122416 AN: 246568 AF XY: 0.495

Gnomad AFR exome AF: 0.214

Gnomad AMR exome AF: 0.710

Gnomad ASJ exome AF: 0.503

Gnomad EAS exome AF: 0.428

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.474

Gnomad OTH exome AF: 0.498

GnomAD4 exome AF: 0.479 AC: 697589 AN: 1456826 Hom.: 170403 Cov.: 54 AF XY: 0.481 AC XY: 348479 AN XY: 724882

African (AFR) AF: 0.208 AC: 6874 AN: 33098

American (AMR) AF: 0.692 AC: 30076 AN: 43448

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 13059 AN: 25844

East Asian (EAS) AF: 0.425 AC: 16847 AN: 39658

South Asian (SAS) AF: 0.517 AC: 44511 AN: 86084

European-Finnish (FIN) AF: 0.515 AC: 27059 AN: 52498

Middle Eastern (MID) AF: 0.524 AC: 3007 AN: 5738

European-Non Finnish (NFE) AF: 0.476 AC: 528036 AN: 1110316

Other (OTH) AF: 0.468 AC: 28120 AN: 60142

GnomAD4 genome AF: 0.418 AC: 63566 AN: 152070 Hom.: 14587 Cov.: 33 AF XY: 0.423 AC XY: 31422 AN XY: 74306

African (AFR) AF: 0.222 AC: 9225 AN: 41512

American (AMR) AF: 0.583 AC: 8905 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1739 AN: 3472

East Asian (EAS) AF: 0.438 AC: 2251 AN: 5142

South Asian (SAS) AF: 0.495 AC: 2381 AN: 4810

European-Finnish (FIN) AF: 0.512 AC: 5420 AN: 10582

Middle Eastern (MID) AF: 0.524 AC: 154 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32279 AN: 67960

Other (OTH) AF: 0.426 AC: 899 AN: 2112

Alfa AF: 0.465 Hom.: 25402

Bravo AF: 0.417

TwinsUK AF: 0.471 AC: 1747

ALSPAC AF: 0.468 AC: 1802

ESP6500AA AF: 0.222 AC: 979

ESP6500EA AF: 0.474 AC: 4076

ExAC AF: 0.481 AC: 58401

Asia WGS AF: 0.457 AC: 1589 AN: 3478

EpiCase AF: 0.475

EpiControl AF: 0.472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.5
DANN	Benign	0.81
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0000056	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L
PhyloP100		-2.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.15
Sift	Benign	0.65	T
Sift4G	Benign	0.40	T
Polyphen		0.24	B
Vest4		0.056
MPC		0.12
ClinPred		0.0020	T
GERP RS		-0.62
Varity_R		0.044
gMVP		0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3764645; hg19: chr19-1042809; COSMIC: COSV54025202; COSMIC: COSV54025202;