rs41382345

Variant names:

• chr19-44908712-A-G
• NM_000041.4:c.416A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-44908712-A-G
• chr19-44908712-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000041.4(APOE):​c.416A>G​(p.Glu139Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4	c.416A>G	p.Glu139Gly	missense_variant	Exon 4 of 4	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.416A>G	p.Glu139Gly	missense_variant	Exon 4 of 4	1	NM_000041.4	ENSP00000252486.3
APOE	ENST00000425718.1	c.416A>G	p.Glu139Gly	missense_variant	Exon 3 of 3	1		ENSP00000410423.1
APOE	ENST00000434152.5	c.494A>G	p.Glu165Gly	missense_variant	Exon 4 of 4	2		ENSP00000413653.2
APOE	ENST00000446996.5	c.416A>G	p.Glu139Gly	missense_variant	Exon 4 of 4	2		ENSP00000413135.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Aug 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.416A>G (p.E139G) alteration is located in exon 4 (coding exon 3) of the APOE gene. This alteration results from a A to G substitution at nucleotide position 416, causing the glutamic acid (E) at amino acid position 139 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.9	D;D;.;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.60
MutPred		0.71		Gain of MoRF binding (P = 0.0474);Gain of MoRF binding (P = 0.0474);.;Gain of MoRF binding (P = 0.0474);
MVP		0.96
MPC		1.7
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.59
gMVP		0.74

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-45411969;