chr19-1043749-A-G

Variant names:

• chr19-1043749-A-G
• rs3752232
• NM_019112.4:c.955A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_019112.4(ABCA7):​c.955A>G​(p.Thr319Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0507 in 1,612,638 control chromosomes in the GnomAD database, including 3,836 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.097 (1359 hom., cov: 30)
  • Exomes 𝑓: 0.046 (2477 hom.)
• Consequence: ABCA7 NM_019112.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• Publications: 37 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003932923).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.241 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.955A>G	p.Thr319Ala	missense	Exon 10 of 47	NP_061985.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA7	ENST00000263094.11	TSL:5 MANE Select	c.955A>G	p.Thr319Ala	missense	Exon 10 of 47	ENSP00000263094.6
	ABCA7	ENST00000433129.6	TSL:1	n.1635A>G		non_coding_transcript_exon	Exon 9 of 44

Frequencies

GnomAD3 genomes AF: 0.0968 AC: 14673 AN: 151576 Hom.: 1351 Cov.: 30

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.0415

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.0898

Gnomad SAS AF: 0.0523

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0399

Gnomad OTH AF: 0.0703

GnomAD2 exomes AF: 0.0548 AC: 13709 AN: 250038 AF XY: 0.0513

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0241

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.0862

Gnomad FIN exome AF: 0.0282

Gnomad NFE exome AF: 0.0403

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0459 AC: 67112 AN: 1460944 Hom.: 2477 Cov.: 34 AF XY: 0.0452 AC XY: 32820 AN XY: 726684

African (AFR) AF: 0.250 AC: 8385 AN: 33480

American (AMR) AF: 0.0265 AC: 1186 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 722 AN: 26136

East Asian (EAS) AF: 0.0738 AC: 2930 AN: 39698

South Asian (SAS) AF: 0.0501 AC: 4322 AN: 86252

European-Finnish (FIN) AF: 0.0276 AC: 1448 AN: 52552

Middle Eastern (MID) AF: 0.0182 AC: 105 AN: 5768

European-Non Finnish (NFE) AF: 0.0402 AC: 44731 AN: 1111946

Other (OTH) AF: 0.0544 AC: 3283 AN: 60390

GnomAD4 genome AF: 0.0970 AC: 14719 AN: 151694 Hom.: 1359 Cov.: 30 AF XY: 0.0958 AC XY: 7099 AN XY: 74126

African (AFR) AF: 0.245 AC: 10088 AN: 41232

American (AMR) AF: 0.0413 AC: 630 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 100 AN: 3462

East Asian (EAS) AF: 0.0898 AC: 463 AN: 5154

South Asian (SAS) AF: 0.0525 AC: 252 AN: 4798

European-Finnish (FIN) AF: 0.0300 AC: 317 AN: 10568

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0399 AC: 2708 AN: 67942

Other (OTH) AF: 0.0715 AC: 150 AN: 2098

Alfa AF: 0.0572 Hom.: 1614

Bravo AF: 0.105

TwinsUK AF: 0.0464 AC: 172

ALSPAC AF: 0.0423 AC: 163

ESP6500AA AF: 0.254 AC: 1119

ESP6500EA AF: 0.0408 AC: 351

ExAC AF: 0.0599 AC: 7276

Asia WGS AF: 0.0870 AC: 304 AN: 3478

EpiCase AF: 0.0366

EpiControl AF: 0.0349

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.0
DANN	Benign	0.62
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.034	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N
PhyloP100		1.6
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.13
Sift	Benign	0.88	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.0080
MPC		0.10
ClinPred		0.0000096	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.32
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3752232; hg19: chr19-1043748; COSMIC: COSV54030168; COSMIC: COSV54030168;