chr19-1042831-G-A

Variant names:

• chr19-1042831-G-A
• rs113465431
• NM_019112.4:c.579+5G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP6_Moderate BS1

The NM_019112.4(ABCA7):​c.579+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000586 in 1,586,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: ABCA7 NM_019112.4 splice_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.16
• Publications: 0 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 -5 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 19-1042831-G-A is Benign according to our data. Variant chr19-1042831-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 715540.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000138 (21/152302) while in subpopulation EAS AF = 0.00231 (12/5184). AF 95% confidence interval is 0.00134. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.579+5G>A		splice_region intron	N/A	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.579+5G>A		splice_region intron	N/A	ENSP00000263094.6	Q8IZY2-1
	ABCA7	ENST00000433129.6	TSL:1	n.1259+5G>A		splice_region intron	N/A
	ABCA7	ENST00000526885.5	TSL:1	n.*87G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000326 AC: 74 AN: 227162 AF XY: 0.000298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000351

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00416

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000187

GnomAD4 exome AF: 0.0000502 AC: 72 AN: 1434122 Hom.: 0 Cov.: 34 AF XY: 0.0000505 AC XY: 36 AN XY: 712360

African (AFR) AF: 0.0000312 AC: 1 AN: 32070

American (AMR) AF: 0.0000261 AC: 1 AN: 38310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24102

East Asian (EAS) AF: 0.00160 AC: 63 AN: 39432

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1099654

Other (OTH) AF: 0.0000339 AC: 2 AN: 58998

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74456

African (AFR) AF: 0.000168 AC: 7 AN: 41566

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000401 Hom.: 0

Bravo AF: 0.000185

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.72
PhyloP100		1.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.020		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: rs113465431; hg19: chr19-1042830;