rs3752246

Positions:

• chr19-1056493-G-C
• chr19-1056493-G-T

Variant summary

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

The NM_019112.4(ABCA7):​c.4580G>C​(p.Gly1527Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.831 in 1,612,048 control chromosomes in the GnomAD database, including 559,162 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 0.86 (57037 hom., cov: 31)
  • Exomes 𝑓: 0.83 (502125 hom.)
• Consequence: ABCA7 NM_019112.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.147

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3769012E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.95 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA7	NM_019112.4	c.4580G>C	p.Gly1527Ala	missense_variant	33/47	ENST00000263094.11	NP_061985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA7	ENST00000263094.11	c.4580G>C	p.Gly1527Ala	missense_variant	33/47	5	NM_019112.4	ENSP00000263094	P1
ABCA7	ENST00000433129.6	n.4880G>C		non_coding_transcript_exon_variant	30/44	1
ABCA7	ENST00000673773.1	n.423G>C		non_coding_transcript_exon_variant	2/11
ABCA7	ENST00000435683.7	c.*463G>C		3_prime_UTR_variant, NMD_transcript_variant	16/29	5		ENSP00000465322

Frequencies

GnomAD3 genomes AF: 0.862 AC: 131155 AN: 152064 Hom.: 56979 Cov.: 31

Gnomad AFR AF: 0.957

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.868

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.807

Gnomad FIN AF: 0.885

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.839

GnomAD3 exomes AF: 0.840 AC: 207104 AN: 246680 Hom.: 87533 AF XY: 0.836 AC XY: 111976 AN XY: 133892

Gnomad AFR exome AF: 0.962

Gnomad AMR exome AF: 0.904

Gnomad ASJ exome AF: 0.809

Gnomad EAS exome AF: 0.646

Gnomad SAS exome AF: 0.832

Gnomad FIN exome AF: 0.885

Gnomad NFE exome AF: 0.830

Gnomad OTH exome AF: 0.836

GnomAD4 exome AF: 0.828 AC: 1208802 AN: 1459866 Hom.: 502125 Cov.: 67 AF XY: 0.828 AC XY: 601248 AN XY: 726214

Gnomad4 AFR exome AF: 0.964

Gnomad4 AMR exome AF: 0.899

Gnomad4 ASJ exome AF: 0.812

Gnomad4 EAS exome AF: 0.642

Gnomad4 SAS exome AF: 0.834

Gnomad4 FIN exome AF: 0.885

Gnomad4 NFE exome AF: 0.825

Gnomad4 OTH exome AF: 0.826

GnomAD4 genome AF: 0.863 AC: 131264 AN: 152182 Hom.: 57037 Cov.: 31 AF XY: 0.864 AC XY: 64277 AN XY: 74392

Gnomad4 AFR AF: 0.957

Gnomad4 AMR AF: 0.868

Gnomad4 ASJ AF: 0.811

Gnomad4 EAS AF: 0.666

Gnomad4 SAS AF: 0.807

Gnomad4 FIN AF: 0.885

Gnomad4 NFE AF: 0.827

Gnomad4 OTH AF: 0.831

Alfa AF: 0.842 Hom.: 12149

Bravo AF: 0.865

TwinsUK AF: 0.815 AC: 3021

ALSPAC AF: 0.828 AC: 3190

ESP6500AA AF: 0.956 AC: 4214

ESP6500EA AF: 0.829 AC: 7127

ExAC AF: 0.838 AC: 101568

Asia WGS AF: 0.727 AC: 2530 AN: 3478

EpiCase AF: 0.828

EpiControl AF: 0.824

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.039
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.67
DANN	Benign	0.20
DEOGEN2	Benign	0.15	T;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.36	T;.;T
MetaRNN	Benign	0.0000014	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.6	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	2.7	N;N;.
REVEL	Benign	0.18
Sift	Benign	0.88	T;T;.
Sift4G	Benign	0.91	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.013
MPC		0.11
ClinPred		0.000015	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.16

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: rs3752246; hg19: chr19-1056492; COSMIC: COSV54034249; COSMIC: COSV54034249;