rs4147918

chr19-1058177-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_019112.4(ABCA7):c.5057A>G(p.Gln1686Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.043 in 1,613,750 control chromosomes in the GnomAD database, including 1,989 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.035 (179 hom., cov: 32)
  • Exomes 𝑓: 0.044 (1810 hom.)
• Consequence: ABCA7 NM_019112.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.573

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013472438).
• BP6: Variant 19-1058177-A-G is Benign according to our data. Variant chr19-1058177-A-G is described in ClinVar as [Benign]. Clinvar id is 1246709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA7	NM_019112.4	c.5057A>G	p.Gln1686Arg	missense_variant	37/47	ENST00000263094.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA7	ENST00000263094.11	c.5057A>G	p.Gln1686Arg	missense_variant	37/47	5	NM_019112.4	P1

Frequencies

GnomAD3 genomes AF: 0.0354 AC: 5370 AN: 151868 Hom.: 179 Cov.: 32

Gnomad AFR AF: 0.00745

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0208

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.0637

Gnomad FIN AF: 0.0594

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0405

Gnomad OTH AF: 0.0274

GnomAD3 exomes AF: 0.0478 AC: 11991 AN: 251102 Hom.: 454 AF XY: 0.0491 AC XY: 6673 AN XY: 135832

Gnomad AFR exome AF: 0.00665

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.0280

Gnomad EAS exome AF: 0.166

Gnomad SAS exome AF: 0.0641

Gnomad FIN exome AF: 0.0582

Gnomad NFE exome AF: 0.0413

Gnomad OTH exome AF: 0.0364

GnomAD4 exome AF: 0.0438 AC: 63973 AN: 1461762 Hom.: 1810 Cov.: 32 AF XY: 0.0442 AC XY: 32121 AN XY: 727156

Gnomad4 AFR exome AF: 0.00603

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0282

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.0622

Gnomad4 FIN exome AF: 0.0558

Gnomad4 NFE exome AF: 0.0409

Gnomad4 OTH exome AF: 0.0451

GnomAD4 genome AF: 0.0353 AC: 5372 AN: 151988 Hom.: 179 Cov.: 32 AF XY: 0.0372 AC XY: 2767 AN XY: 74296

Gnomad4 AFR AF: 0.00743

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.0638

Gnomad4 FIN AF: 0.0594

Gnomad4 NFE AF: 0.0405

Gnomad4 OTH AF: 0.0290

Alfa AF: 0.0404 Hom.: 217

Bravo AF: 0.0309

TwinsUK AF: 0.0456 AC: 169

ALSPAC AF: 0.0449 AC: 173

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.0413 AC: 355

ExAC AF: 0.0478 AC: 5798

Asia WGS AF: 0.107 AC: 371 AN: 3478

EpiCase AF: 0.0370

EpiControl AF: 0.0354

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ABCA7-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 22, 2019

This variant is associated with the following publications: (PMID: 31182772, 30917570) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	1.8
Dann	Benign	0.84
DEOGEN2	Benign	0.21	T;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.58	T;.;T
MetaRNN	Benign	0.0013	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.23	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.44	N;N;.
REVEL	Benign	0.15
Sift	Benign	0.23	T;T;.
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.025
MPC		0.11
ClinPred		0.00077	T
GERP RS		-4.3
Varity_R		0.062
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs4147918; hg19: chr19-1058176; COSMIC: COSV54029338; COSMIC: COSV54029338;