19-44908730-G-T

Variant names:

• chr19-44908730-G-T
• NM_000041.4:c.434G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000041.4(APOE):​c.434G>T​(p.Gly145Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.98

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4	c.434G>T	p.Gly145Val	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.434G>T	p.Gly145Val	missense_variant	Exon 4 of 4	1	NM_000041.4	ENSP00000252486.3
APOE	ENST00000425718.1	c.434G>T	p.Gly145Val	missense_variant	Exon 3 of 3	1		ENSP00000410423.1
APOE	ENST00000434152.5	c.512G>T	p.Gly171Val	missense_variant	Exon 4 of 4	2		ENSP00000413653.2
APOE	ENST00000446996.5	c.434G>T	p.Gly145Val	missense_variant	Exon 4 of 4	2		ENSP00000413135.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408146 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 695816

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.21e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;T;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.070	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D;D;.;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0050	D;D;.;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.45
MutPred		0.85		Loss of disorder (P = 0.073);Loss of disorder (P = 0.073);.;Loss of disorder (P = 0.073);
MVP		0.95
MPC		1.8
ClinPred		0.98	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.65
gMVP		0.38

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: chr19-45411987;