17-66214462-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000042.3(APOH):​c.973T>A​(p.Cys325Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. C325G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

APOH
NM_000042.3 missense

Scores

12
5
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.76
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 made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APOHNM_000042.3 linkc.973T>A p.Cys325Ser missense_variant Exon 7 of 8 ENST00000205948.11 NP_000033.2 P02749A0A384NKM6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APOHENST00000205948.11 linkc.973T>A p.Cys325Ser missense_variant Exon 7 of 8 1 NM_000042.3 ENSP00000205948.6 P02749
APOHENST00000585162.1 linkc.257-2274T>A intron_variant Intron 2 of 2 2 ENSP00000462260.1 J3KS17

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.47
T
Eigen
Pathogenic
0.75
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.72
T
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.8
M
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-6.6
D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.65
MutPred
0.76
Gain of disorder (P = 0.0092);
MVP
0.98
MPC
0.74
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.93
gMVP
0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-64210580; API