rs201060968

Variant names:

• chr19-1054256-G-A
• rs201060968
• NM_019112.4:c.3641G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1054256-G-A
• chr19-1054256-G-C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_019112.4(ABCA7):​c.3641G>A​(p.Trp1214*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000272 in 1,609,026 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (3 hom.)
• Consequence: ABCA7 NM_019112.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• Conservation: PhyloP100: 5.81
• Publications: 9 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: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 19-1054256-G-A is Benign according to our data. Variant chr19-1054256-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225545.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000388 (59/152024) while in subpopulation EAS AF = 0.00388 (20/5150). AF 95% confidence interval is 0.00257. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA7	NM_019112.4	MANE Select	c.3641G>A	p.Trp1214*	stop_gained	Exon 27 of 47	NP_061985.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA7	ENST00000263094.11	TSL:5 MANE Select	c.3641G>A	p.Trp1214*	stop_gained	Exon 27 of 47	ENSP00000263094.6
	ABCA7	ENST00000433129.6	TSL:1	n.4321G>A		non_coding_transcript_exon	Exon 26 of 44
	ABCA7	ENST00000435683.7	TSL:5	n.1112G>A		non_coding_transcript_exon	Exon 10 of 29	ENSP00000465322.2

Frequencies

GnomAD3 genomes AF: 0.000395 AC: 60 AN: 151906 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00664

Gnomad EAS AF: 0.00407

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000635 AC: 151 AN: 237926 AF XY: 0.000626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00677

Gnomad EAS exome AF: 0.00390

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.000514

GnomAD4 exome AF: 0.000260 AC: 379 AN: 1457002 Hom.: 3 Cov.: 35 AF XY: 0.000266 AC XY: 193 AN XY: 724874

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00675 AC: 176 AN: 26076

East Asian (EAS) AF: 0.00199 AC: 79 AN: 39666

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000720 AC: 80 AN: 1111186

Other (OTH) AF: 0.000664 AC: 40 AN: 60204

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74286

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.000262 AC: 4 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00664 AC: 23 AN: 3466

East Asian (EAS) AF: 0.00388 AC: 20 AN: 5150

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67964

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.000740 Hom.: 6

Bravo AF: 0.000366

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.000480 AC: 58

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	-	Alzheimer disease 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.8
Vest4		0.68
GERP RS		3.6
Mutation Taster		=26/174	disease causing (fs/PTC)

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: rs201060968; hg19: chr19-1054255;