19-44907654-T-G

Position:

• chr19-44907654-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000041.4(APOE):​c.44-106T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00613 in 992,904 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (21 hom.)
• Consequence: APOE NM_000041.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.652

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-44907654-T-G is Benign according to our data. Variant chr19-44907654-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00516 (786/152280) while in subpopulation NFE AF= 0.00769 (523/68020). AF 95% confidence interval is 0.00714. There are 3 homozygotes in gnomad4. There are 383 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOE	NM_000041.4	c.44-106T>G		intron_variant		ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.44-106T>G		intron_variant		1	NM_000041.4	ENSP00000252486	P1
APOE	ENST00000425718.1	c.44-106T>G		intron_variant		1		ENSP00000410423
APOE	ENST00000434152.5	c.122-106T>G		intron_variant		2		ENSP00000413653
APOE	ENST00000446996.5	c.44-106T>G		intron_variant		2		ENSP00000413135

Frequencies

GnomAD3 genomes AF: 0.00516 AC: 785 AN: 152162 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00769

Gnomad OTH AF: 0.00431

GnomAD4 exome AF: 0.00630 AC: 5297 AN: 840624 Hom.: 21 AF XY: 0.00601 AC XY: 2603 AN XY: 433380

Gnomad4 AFR exome AF: 0.00181

Gnomad4 AMR exome AF: 0.00516

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.00467

Gnomad4 NFE exome AF: 0.00787

Gnomad4 OTH exome AF: 0.00465

GnomAD4 genome AF: 0.00516 AC: 786 AN: 152280 Hom.: 3 Cov.: 32 AF XY: 0.00514 AC XY: 383 AN XY: 74454

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00650

Gnomad4 NFE AF: 0.00769

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00526 Hom.: 0

Bravo AF: 0.00478

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs769451; hg19: chr19-45410911;