19-44907806-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_000041.4(APOE):c.90C>G(p.Pro30=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 1,613,602 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: APOE NM_000041.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -2.47

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-44907806-C-G is Benign according to our data. Variant chr19-44907806-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1209987.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-44907806-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.47 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4	c.90C>G	p.Pro30=	synonymous_variant	3/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.90C>G	p.Pro30=	synonymous_variant	3/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.90C>G	p.Pro30=	synonymous_variant	2/3	1
APOE	ENST00000434152.5	c.168C>G	p.Pro56=	synonymous_variant	3/4	2
APOE	ENST00000446996.5	c.90C>G	p.Pro30=	synonymous_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000116 AC: 29 AN: 249392 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 135124

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000472

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000304 AC: 445 AN: 1461446 Hom.: 0 Cov.: 32 AF XY: 0.000290 AC XY: 211 AN XY: 727030

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000384

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74342

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000151

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.056
Dann	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs370227413; hg19: chr19-45411063; COSMIC: COSV52986204; COSMIC: COSV52986204;