19-44907807-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000041.4(APOE):c.91G>A(p.Glu31Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter P:1 B:1
• Conservation: PhyloP100: 1.54

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03719899).
• BP6: Variant 19-44907807-G-A is Benign according to our data. Variant chr19-44907807-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 440842.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000473 (72/152304) while in subpopulation AMR AF= 0.00314 (48/15302). AF 95% confidence interval is 0.00243. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOE	NM_000041.4	c.91G>A	p.Glu31Lys	missense_variant	3/4	ENST00000252486.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOE	ENST00000252486.9	c.91G>A	p.Glu31Lys	missense_variant	3/4	1	NM_000041.4	P1
APOE	ENST00000425718.1	c.91G>A	p.Glu31Lys	missense_variant	2/3	1
APOE	ENST00000434152.5	c.169G>A	p.Glu57Lys	missense_variant	3/4	2
APOE	ENST00000446996.5	c.91G>A	p.Glu31Lys	missense_variant	3/4	2

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 249636 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135246

Gnomad AFR exome AF: 0.000250

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000235

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000575 AC: 84 AN: 1461496 Hom.: 0 Cov.: 32 AF XY: 0.0000536 AC XY: 39 AN XY: 727060

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74474

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000176 Hom.: 0

Bravo AF: 0.00102

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

APOE5 VARIANT Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1991

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2019

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.090
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.64	T;T;T;T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.037	T;T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.8	L;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.99	N;N;.;N
REVEL	Uncertain	0.42
Sift	Benign	0.052	T;T;.;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.0050	B;.;.;.
Vest4		0.76
MVP		0.90
MPC		0.69
ClinPred		0.011	T
GERP RS		1.5
Varity_R		0.092
gMVP		0.30

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: rs201672011; hg19: chr19-45411064;