chr19-44905910-C-T

Variant names:

• chr19-44905910-C-T
• rs440446
• NM_000041.4:c.-24+69C>T

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP7

The NM_001302688.2(APOE):c.42C>T (p.Asn14Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. Note: NM_001302688.2 is not a MANE Select or MANE Plus Clinical transcript for APOE; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.00000309 (AC=4) in the gnomAD database across 1,294,726 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000659. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: APOE NM_001302688.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.66
• Publications: 121 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: Unknown, AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hyperlipoproteinemia type 3

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

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

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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000659 — very rare for AD+AR gene (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP7Synonymous variant, no splicing impact		Synonymous variant at non-conserved position with no predicted splicing impact (BP7); Synonymous at non-conserved position, no splicing concern — benign (BP7).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001302688.2. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	APOE NM_000041.4	MANE Select	c.-24+69C>T	intron	Intron 1 of 3	Prot: NP_000032.1 UniProt:
	APOE NM_001302688.2		c.42C>T p.Asn14Asn	synonymous	Exon 1 of 4	Prot: NP_001289617.1
	APOE NM_001302691.2		c.-39+69C>T	intron	Intron 1 of 3	Prot: NP_001289620.1 UniProt:

APOE NM_000041.4

MANE Select

HGVSc / HGVSpc.-24+69C>T

Exon rankIntron 1 of 3

intron

Prot: NP_000032.1UniProt: P02649A0A0S2Z3D5

APOE NM_001302688.2

HGVSc / HGVSpc.42C>Tp.Asn14Asn

Exon rankExon 1 of 4

synonymous

Prot: NP_001289617.1

APOE NM_001302691.2

HGVSc / HGVSpc.-39+69C>T

Exon rankIntron 1 of 3

intron

Prot: NP_001289620.1UniProt: A0A0S2Z3D5P02649

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	APOE ENST00000252486.9	TSL:1MANE Select	c.-24+69C>T	intron	Intron 1 of 3	Prot: ENSP00000252486.3 UniProt:
	APOE ENST00000485628.2	TSL:1	n.46+69C>T	intron	Intron 1 of 1	Prot:
	APOE ENST00000434152.5	TSL:2	c.42C>T p.Asn14Asn	synonymous	Exon 1 of 4	Prot: ENSP00000413653.2 UniProt:

APOE ENST00000252486.9

TSL:1MANE Select

HGVSc / HGVSpc.-24+69C>T

Exon rankIntron 1 of 3

intron

Prot: ENSP00000252486.3UniProt: P02649

APOE ENST00000485628.2

TSL:1

HGVSc / HGVSpn.46+69C>T

Exon rankIntron 1 of 1

intron

Prot:

APOE ENST00000434152.5

TSL:2

HGVSc / HGVSpc.42C>Tp.Asn14Asn

Exon rankExon 1 of 4

synonymous

Prot: ENSP00000413653.2UniProt: H0Y7L5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000659	AC:1	Hom:0	AN:151776	Cov:29
GnomAD4 exome	AF: 0.00000262	AC:3	Hom:0	AN:1142950	Cov:41
GnomAD4 genome	AF: 0.00000659	AC:1	Hom:0	AN:151776	Cov:29
TOPMed (Bravo)	AF: 0.0000189	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:8733	AN:41952	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	31834	0.0000122	1	81804

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.22
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.1
DANN	Benign	0.93
GPN-Star LLR	N/A	2.0
GPN-Star score	N/A	-2.0
PhyloP100	Benign	-2.7
PromoterAI	N/A	-0.056	Neutral
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.0

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs440446;

hg19: chr19-45409167;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar