19-44907864-C-T

Variant names:

• chr19-44907864-C-T
• rs11542029
• NM_000041.4:c.148C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000041.4(APOE):​c.148C>T​(p.Arg50Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,720 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: 0.0000041 (0 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44

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 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOE	NM_000041.4	c.148C>T	p.Arg50Cys	missense_variant	Exon 3 of 4	ENST00000252486.9	NP_000032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOE	ENST00000252486.9	c.148C>T	p.Arg50Cys	missense_variant	Exon 3 of 4	1	NM_000041.4	ENSP00000252486.3
APOE	ENST00000425718.1	c.148C>T	p.Arg50Cys	missense_variant	Exon 2 of 3	1		ENSP00000410423.1
APOE	ENST00000434152.5	c.226C>T	p.Arg76Cys	missense_variant	Exon 3 of 4	2		ENSP00000413653.2
APOE	ENST00000446996.5	c.148C>T	p.Arg50Cys	missense_variant	Exon 3 of 4	2		ENSP00000413135.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250808 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135688

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461720 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727142

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	0.0073	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.85	D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Pathogenic	3.2	M;.;.;.
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.0	D;D;.;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.61
MutPred		0.58		Loss of MoRF binding (P = 0.0202);Loss of MoRF binding (P = 0.0202);.;Loss of MoRF binding (P = 0.0202);
MVP		0.95
MPC		1.9
ClinPred		0.94	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.72

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: rs11542029; hg19: chr19-45411121;