rs121918398

Variant names:

• chr19-44909171-G-A
• rs121918398
• NM_000041.4:c.875G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-44909171-G-A
• chr19-44909171-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2 PP5

The NM_000041.4(APOE):​c.875G>A​(p.Arg292His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,447,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.230
• Publications: 5 publications found

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]

APOE Gene-Disease associations (from GenCC):

• Alzheimer disease 2

  Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hyperlipoproteinemia type 3

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lipoprotein glomerulopathy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp
• sea-blue histiocyte syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000280087 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.74028 (below the threshold of 3.09). Trascript score misZ: -1.1391 (below the threshold of 3.09). GenCC associations: The gene is linked to hyperlipoproteinemia type 3, sea-blue histiocyte syndrome, lipoprotein glomerulopathy, Alzheimer disease 2.
• PP5: Variant 19-44909171-G-A is Pathogenic according to our data. Variant chr19-44909171-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 17875.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000041.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	NM_000041.4	MANE Select	c.875G>A	p.Arg292His	missense	Exon 4 of 4	NP_000032.1
	APOE	NM_001302688.2		c.953G>A	p.Arg318His	missense	Exon 4 of 4	NP_001289617.1
	APOE	NM_001302689.2		c.875G>A	p.Arg292His	missense	Exon 4 of 4	NP_001289618.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000252486.9	TSL:1 MANE Select	c.875G>A	p.Arg292His	missense	Exon 4 of 4	ENSP00000252486.3
	APOE	ENST00000425718.1	TSL:1	c.*217G>A		downstream_gene	N/A	ENSP00000410423.1
	ENSG00000280087	ENST00000623895.1	TSL:6	n.-204G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000447 AC: 1 AN: 223554 AF XY: 0.00000806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000989

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1447856 Hom.: 0 Cov.: 33 AF XY: 0.00000416 AC XY: 3 AN XY: 720710

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 85958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5520

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110874

Other (OTH) AF: 0.00 AC: 0 AN: 60102

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

APOE4 VARIANT Pathogenic:1

May 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.23
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.25
MutPred		0.44		Loss of MoRF binding (P = 0.021)
MVP		0.90
MPC		1.7
ClinPred		0.74	D
GERP RS		1.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.11
gMVP		0.63
Mutation Taster		=50/50	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121918398; hg19: chr19-45412428;