rs52797880

Positions:

• chr17-66220736-A-C
• chr17-66220736-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000042.3(APOH):​c.422T>G​(p.Ile141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: APOH NM_000042.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14789021).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOH	NM_000042.3	c.422T>G	p.Ile141Ser	missense_variant	5/8	ENST00000205948.11	NP_000033.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOH	ENST00000205948.11	c.422T>G	p.Ile141Ser	missense_variant	5/8	1	NM_000042.3	ENSP00000205948.6
APOH	ENST00000581797.5	c.242T>G	p.Ile81Ser	missense_variant	5/6	3		ENSP00000463553.1
APOH	ENST00000577982.1	c.422T>G	p.Ile141Ser	missense_variant	6/6	5		ENSP00000464301.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.091	T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.24	T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.090	N;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.4	N;.;.
REVEL	Benign	0.090
Sift	Benign	0.15	T;.;.
Sift4G	Benign	0.46	T;.;.
Polyphen		0.0020	B;.;.
Vest4		0.17
MutPred		0.53		Gain of glycosylation at I141 (P = 0.0015);.;Gain of glycosylation at I141 (P = 0.0015);
MVP		0.040
MPC		0.23
ClinPred		0.18	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs52797880; hg19: chr17-64216854;