17-66212173-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000042.3(APOH):​c.998C>A​(p.Ala333Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A333V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

APOH
NM_000042.3 missense

Scores

1
9
9

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.88

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]

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ACMG classification

Classification was made for transcript

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

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APOHNM_000042.3 linkc.998C>A p.Ala333Asp missense_variant Exon 8 of 8 ENST00000205948.11 NP_000033.2 P02749A0A384NKM6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APOHENST00000205948.11 linkc.998C>A p.Ala333Asp missense_variant Exon 8 of 8 1 NM_000042.3 ENSP00000205948.6 P02749
APOHENST00000585162.1 linkc.272C>A p.Ala91Asp missense_variant Exon 3 of 3 2 ENSP00000462260.1 J3KS17

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461482
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727080
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33468
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39672
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86242
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53412
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111678
Other (OTH)
AF:
0.00
AC:
0
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.70
BayesDel_addAF
Uncertain
0.024
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
T
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.72
T
M_CAP
Benign
0.0090
T
MetaRNN
Uncertain
0.63
D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.4
M
PhyloP100
4.9
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-2.1
N
REVEL
Benign
0.16
Sift
Benign
0.11
T
Sift4G
Uncertain
0.0040
D
Polyphen
0.92
P
Vest4
0.50
MutPred
0.64
Gain of solvent accessibility (P = 0.0156);
MVP
0.27
MPC
0.65
ClinPred
0.96
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.35
gMVP
0.48
Mutation Taster
=66/34
polymorphism

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

Other links and lift over

dbSNP: rs780277635; hg19: chr17-64208291; API