chr19-44905923-G-A

Position:

• chr19-44905923-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000041.4(APOE):​c.-24+82G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000622 in 1,296,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: APOE NM_000041.4 intron
• Scores: Splicing: ADA: 0.00009908
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 0.250

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00725469).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000572 (87/152180) while in subpopulation NFE AF= 0.000779 (53/68002). AF 95% confidence interval is 0.000612. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4	c.-24+82G>A		intron_variant		ENST00000252486.9
APOE	NM_001302688.2	c.55G>A	p.Asp19Asn	missense_variant, splice_region_variant	1/4
APOE	NM_001302691.2	c.-39+82G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.-24+82G>A		intron_variant		1	NM_000041.4	P1
APOE	ENST00000485628.2	n.46+82G>A		intron_variant, non_coding_transcript_variant		1
APOE	ENST00000434152.5	c.55G>A	p.Asp19Asn	missense_variant, splice_region_variant	1/4	2
APOE	ENST00000446996.5	c.-39+82G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152062 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000583 AC: 82 AN: 140542 Hom.: 0 AF XY: 0.000656 AC XY: 50 AN XY: 76164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000345

Gnomad ASJ exome AF: 0.00412

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000330

Gnomad NFE exome AF: 0.000598

Gnomad OTH exome AF: 0.00124

GnomAD4 exome AF: 0.000628 AC: 719 AN: 1144028 Hom.: 0 Cov.: 32 AF XY: 0.000585 AC XY: 328 AN XY: 561122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000372

Gnomad4 ASJ exome AF: 0.00493

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000220

Gnomad4 NFE exome AF: 0.000646

Gnomad4 OTH exome AF: 0.000802

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152180 Hom.: 0 Cov.: 30 AF XY: 0.000497 AC XY: 37 AN XY: 74388

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000955 Hom.: 0

Bravo AF: 0.000631

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.000811 AC: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alzheimer disease 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centogene AG - the Rare Disease Company

Sep 02, 2020

- -

APOE-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 12, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.4
DANN	Benign	0.76
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N
REVEL	Benign	0.0080
MVP		0.69
ClinPred		0.0074	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000099
dbscSNV1_RF	Benign	0.0080
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: rs563571689; hg19: chr19-45409180;