NM_000041.4:c.388T>C

Variant names:

• chr19-44908684-T-C
• rs429358
• NM_000041.4:c.388T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP4_Strong BA1

The NM_000041.4(APOE):​c.388T>C​(p.Cys130Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,567,892 control chromosomes in the GnomAD database, including 17,710 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.16 (2010 hom., cov: 32)
  • Exomes 𝑓: 0.15 (15700 hom.)
• Consequence: APOE NM_000041.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other; risk factor criteria provided, conflicting classifications P:6 U:5 B:1 O:4
• Conservation: PhyloP100: 0.840
• Publications: 3290 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a region_of_interest 8 X 22 AA approximate tandem repeats (size 175) in uniprot entity APOE_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_000041.4
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0037242472).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.212 is higher than 0.05.

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.388T>C	p.Cys130Arg	missense	Exon 4 of 4	NP_000032.1
	APOE	NM_001302688.2		c.466T>C	p.Cys156Arg	missense	Exon 4 of 4	NP_001289617.1
	APOE	NM_001302689.2		c.388T>C	p.Cys130Arg	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.388T>C	p.Cys130Arg	missense	Exon 4 of 4	ENSP00000252486.3
	APOE	ENST00000425718.1	TSL:1	c.388T>C	p.Cys130Arg	missense	Exon 3 of 3	ENSP00000410423.1
	APOE	ENST00000864831.1		c.442T>C	p.Cys148Arg	missense	Exon 5 of 5	ENSP00000534890.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23875 AN: 151972 Hom.: 1998 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.0975

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.0673

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.110

GnomAD2 exomes AF: 0.138 AC: 23502 AN: 169692 AF XY: 0.136

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.0874

Gnomad FIN exome AF: 0.209

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.148 AC: 208931 AN: 1415800 Hom.: 15700 Cov.: 34 AF XY: 0.146 AC XY: 102105 AN XY: 700502

African (AFR) AF: 0.227 AC: 7291 AN: 32174

American (AMR) AF: 0.104 AC: 3877 AN: 37182

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3045 AN: 25280

East Asian (EAS) AF: 0.0979 AC: 3591 AN: 36698

South Asian (SAS) AF: 0.100 AC: 8181 AN: 81486

European-Finnish (FIN) AF: 0.191 AC: 9464 AN: 49490

Middle Eastern (MID) AF: 0.0681 AC: 384 AN: 5642

European-Non Finnish (NFE) AF: 0.151 AC: 164927 AN: 1089188

Other (OTH) AF: 0.139 AC: 8171 AN: 58660

GnomAD4 genome AF: 0.157 AC: 23933 AN: 152092 Hom.: 2010 Cov.: 32 AF XY: 0.161 AC XY: 11948 AN XY: 74354

African (AFR) AF: 0.216 AC: 8954 AN: 41512

American (AMR) AF: 0.113 AC: 1734 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3468

East Asian (EAS) AF: 0.0977 AC: 503 AN: 5148

South Asian (SAS) AF: 0.105 AC: 505 AN: 4830

European-Finnish (FIN) AF: 0.195 AC: 2069 AN: 10600

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.138 AC: 9368 AN: 67916

Other (OTH) AF: 0.115 AC: 243 AN: 2116

Alfa AF: 0.0334 Hom.: 751

Bravo AF: 0.155

TwinsUK AF: 0.140 AC: 518

ALSPAC AF: 0.154 AC: 593

ESP6500AA AF: 0.189 AC: 808

ESP6500EA AF: 0.117 AC: 961

ExAC AF: 0.100 AC: 11382

Asia WGS AF: 0.171 AC: 597 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity; other; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	2	-	Alzheimer disease 2 (4)
1	2	-	not provided (5)
1	-	-	Alzheimer disease (2)
1	-	-	Alzheimer disease 4 (1)
-	1	-	Lipoprotein glomerulopathy (1)
-	-	1	not specified (1)
-	-	-	Primary degenerative dementia of the Alzheimer type, presenile onset (1)
-	-	-	Warfarin response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.22
DEOGEN2	Benign	0.099	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PhyloP100		0.84
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	4.4	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.051
MPC		1.1
ClinPred		0.00022	T
GERP RS		3.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		4.0
Varity_R		0.21
gMVP		0.59
Mutation Taster		=89/11	polymorphism (auto)

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: rs429358; hg19: chr19-45411941; COSMIC: COSV52985231; COSMIC: COSV52985231;