dbSNP rs373786395: APOH:p.Pro81Leu (chr17-66226124-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000042.3(APOH):c.242C>T(p.Pro81Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,450,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P81H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

APOH
NM_000042.3 missense, splice_region

Scores

Splicing: ADA: 0.06253

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.36

Publications

2 publications found

Variant links:

Genes affected

APOH (HGNC:616): (apolipoprotein H) Apolipoprotein H, also known as beta-2-glycoprotein I, is a component of circulating plasma lipoproteins. It has been implicated in a variety of physiologic pathways including lipoprotein metabolism, coagulation, hemostasis, and the production of antiphospholipid autoantibodies. APOH may be a required cofactor for anionic phospholipid binding by the antiphospholipid autoantibodies found in sera of many patients with lupus and primary antiphospholipid syndrome (APS). The anti-beta (2) glycoprotein I antibodies from APS patients, mediate inhibition of activated protein C which has anticoagulant properties. Because beta-2-GPI is the main autoantigen in patients with APS, the disruption of this pathway by autoantibodies may be an important mechanism for thrombosis in patients with APS.[provided by RefSeq, Dec 2019]

APOH links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOH	NM_000042.3 link	c.242C>T	p.Pro81Leu	missense_variant, splice_region_variant	Exon 3 of 8	ENST00000205948.11	NP_000033.2	P02749A0A384NKM6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOH	ENST00000205948.11 link	c.242C>T	p.Pro81Leu	missense_variant, splice_region_variant	Exon 3 of 8	1	NM_000042.3	ENSP00000205948.6	P02749
APOH	ENST00000581797.5 link	c.62C>T	p.Pro21Leu	missense_variant, splice_region_variant	Exon 3 of 6	3		ENSP00000463553.1	J3QLI0
APOH	ENST00000577982.1 link	c.242C>T	p.Pro81Leu	missense_variant, splice_region_variant	Exon 4 of 6	5		ENSP00000464301.1	J3QRN2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000410

AC:

AN:

244028

AF XY:

0.00000760

show subpopulations

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:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1450242

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

720882

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33006

American (AMR)

AF:

0.00

AC:

AN:

43140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25840

East Asian (EAS)

AF:

0.00

AC:

AN:

39562

South Asian (SAS)

AF:

0.00

AC:

AN:

83128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1106730

Other (OTH)

AF:

0.00

AC:

AN:

59948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.650

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.60

D;.;T

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.84

T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.9

L;.;.

PhyloP100

5.4

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.3

D;.;.

REVEL

Uncertain

0.60

Sift

Uncertain

0.0050

D;.;.

Sift4G

Uncertain

0.019

D;.;.

Polyphen

1.0

D;.;.

Vest4

0.64

MutPred

0.54

Loss of methylation at K78 (P = 0.0445);.;Loss of methylation at K78 (P = 0.0445);

MVP

0.89

MPC

0.66

ClinPred

0.98

GERP RS

5.5

Varity_R

0.66

gMVP

0.59

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.063

dbscSNV1_RF

Benign

0.26

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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rs373786395

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over