NM_000041.4:c.-23-280C>T

Variant names:

• chr19-44906322-C-T
• rs769448
• NM_000041.4:c.-23-280C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000041.4(APOE):​c.-23-280C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.029 (29 hom., cov: 17)
  • Exomes 𝑓: 0.019 (69 hom.)
• Consequence: APOE NM_000041.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.685
• Publications: 13 publications found

Genes affected

APOE (HGNC:613): (apolipoprotein E) The protein encoded by this gene is a major apoprotein of the chylomicron. It binds to a specific liver and peripheral cell receptor, and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes. Mutations in this gene result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants. [provided by RefSeq, Jun 2016]

APOE Gene-Disease associations (from GenCC):

• Alzheimer disease 2

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hyperlipoproteinemia type 3

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lipoprotein glomerulopathy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp
• sea-blue histiocyte syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-44906322-C-T is Benign according to our data. Variant chr19-44906322-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1329718.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0291 (1955/67166) while in subpopulation NFE AF = 0.0416 (1543/37048). AF 95% confidence interval is 0.0399. There are 29 homozygotes in GnomAd4. There are 860 alleles in the male GnomAd4 subpopulation. Median coverage is 17. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4	c.-23-280C>T		intron_variant	Intron 1 of 3	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.-23-280C>T		intron_variant	Intron 1 of 3	1	NM_000041.4	ENSP00000252486.3

Frequencies

GnomAD3 genomes AF: 0.0291 AC: 1955 AN: 67120 Hom.: 29 Cov.: 17

Gnomad AFR AF: 0.00843

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000477

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.0412

Gnomad MID AF: 0.0116

Gnomad NFE AF: 0.0417

Gnomad OTH AF: 0.0191

GnomAD4 exome AF: 0.0188 AC: 6656 AN: 354092 Hom.: 69 Cov.: 0 AF XY: 0.0181 AC XY: 3371 AN XY: 186710

African (AFR) AF: 0.00298 AC: 31 AN: 10402

American (AMR) AF: 0.00660 AC: 104 AN: 15760

Ashkenazi Jewish (ASJ) AF: 0.00726 AC: 79 AN: 10888

East Asian (EAS) AF: 0.0000422 AC: 1 AN: 23682

South Asian (SAS) AF: 0.0112 AC: 465 AN: 41392

European-Finnish (FIN) AF: 0.0138 AC: 282 AN: 20482

Middle Eastern (MID) AF: 0.00719 AC: 11 AN: 1530

European-Non Finnish (NFE) AF: 0.0253 AC: 5296 AN: 209458

Other (OTH) AF: 0.0189 AC: 387 AN: 20498

GnomAD4 genome AF: 0.0291 AC: 1955 AN: 67166 Hom.: 29 Cov.: 17 AF XY: 0.0284 AC XY: 860 AN XY: 30242

African (AFR) AF: 0.00841 AC: 141 AN: 16764

American (AMR) AF: 0.0225 AC: 92 AN: 4084

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 24 AN: 1980

East Asian (EAS) AF: 0.000477 AC: 1 AN: 2096

South Asian (SAS) AF: 0.0243 AC: 43 AN: 1770

European-Finnish (FIN) AF: 0.0412 AC: 83 AN: 2016

Middle Eastern (MID) AF: 0.0119 AC: 1 AN: 84

European-Non Finnish (NFE) AF: 0.0416 AC: 1543 AN: 37048

Other (OTH) AF: 0.0189 AC: 16 AN: 846

Alfa AF: 0.0181 Hom.: 32

Bravo AF: 0.0129

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 21, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.1
DANN	Benign	0.90
PhyloP100		-0.69
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism

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: rs769448; hg19: chr19-45409579;