Genetic Variant APOH:p.Ile141Asn (chr17-66220736-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000042.3(APOH):c.422T>A(p.Ile141Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

APOH
NM_000042.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.32

Publications

0 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17579463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOH	NM_000042.3 link	c.422T>A	p.Ile141Asn	missense_variant	Exon 5 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.422T>A	p.Ile141Asn	missense_variant	Exon 5 of 8	1	NM_000042.3	ENSP00000205948.6	P02749
APOH	ENST00000581797.5 link	c.242T>A	p.Ile81Asn	missense_variant	Exon 5 of 6	3		ENSP00000463553.1	J3QLI0
APOH	ENST00000577982.1 link	c.422T>A	p.Ile141Asn	missense_variant	Exon 6 of 6	5		ENSP00000464301.1	J3QRN2
APOH	ENST00000585162.1 link	c.-107T>A		upstream_gene_variant		2		ENSP00000462260.1	J3KS17

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1452770

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33284

American (AMR)

AF:

0.00

AC:

AN:

44338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25990

East Asian (EAS)

AF:

0.00

AC:

AN:

39466

South Asian (SAS)

AF:

0.00

AC:

AN:

85654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

9.05e-7

AC:

AN:

1104936

Other (OTH)

AF:

0.00

AC:

AN:

60014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.092

T;.;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.47

T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.46

N;.;.

PhyloP100

2.3

PrimateAI

Benign

0.39

PROVEAN

Benign

1.0

N;.;.

REVEL

Benign

0.060

Sift

Benign

0.20

T;.;.

Sift4G

Benign

0.094

T;.;.

Polyphen

0.30

B;.;.

Vest4

0.23

MutPred

0.53

Gain of catalytic residue at I141 (P = 0.0022);.;Gain of catalytic residue at I141 (P = 0.0022);

MVP

0.055

MPC

0.28

ClinPred

0.19

GERP RS

3.4

PromoterAI

-0.018

Neutral

(source)

Varity_R

0.33

gMVP

0.50

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over