17-66220697-C-A

Variant names:

• chr17-66220697-C-A
• rs8178847
• NM_000042.3:c.461G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000042.3(APOH):​c.461G>T​(p.Arg154Leu) 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. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R154H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: APOH NM_000042.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0800
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053149015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APOH	NM_000042.3	c.461G>T	p.Arg154Leu	missense_variant	Exon 5 of 8	ENST00000205948.11	NP_000033.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOH	ENST00000205948.11	c.461G>T	p.Arg154Leu	missense_variant	Exon 5 of 8	1	NM_000042.3	ENSP00000205948.6
APOH	ENST00000581797.5	c.281G>T	p.Arg94Leu	missense_variant	Exon 5 of 6	3		ENSP00000463553.1
APOH	ENST00000577982.1	c.461G>T	p.Arg154Leu	missense_variant	Exon 6 of 6	5		ENSP00000464301.1
APOH	ENST00000585162.1	c.-68G>T		upstream_gene_variant		2		ENSP00000462260.1

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	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.64
DEOGEN2	Benign	0.080	T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.053	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.;.
PhyloP100		0.080
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.47	N;.;.
REVEL	Benign	0.14
Sift	Benign	0.42	T;.;.
Sift4G	Benign	0.21	T;.;.
Polyphen		0.0030	B;.;.
Vest4		0.21
MutPred		0.41		Gain of ubiquitination at K157 (P = 0.0444);.;Gain of ubiquitination at K157 (P = 0.0444);
MVP		0.20
MPC		0.20
ClinPred		0.075	T
GERP RS		1.6
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.071
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs8178847; hg19: chr17-64216815;