17-66220697-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000042.3(APOH):c.461G>A(p.Arg154His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0663 in 1,612,878 control chromosomes in the GnomAD database, including 3,735 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.073 (427 hom., cov: 31)
  • Exomes 𝑓: 0.066 (3308 hom.)
• Consequence: APOH NM_000042.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0800

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018351972).
• BP6: Variant 17-66220697-C-T is Benign according to our data. Variant chr17-66220697-C-T is described in ClinVar as [Benign]. Clinvar id is 1239878.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOH	NM_000042.3	c.461G>A	p.Arg154His	missense_variant	5/8	ENST00000205948.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOH	ENST00000205948.11	c.461G>A	p.Arg154His	missense_variant	5/8	1	NM_000042.3	P1
APOH	ENST00000581797.5	c.281G>A	p.Arg94His	missense_variant	5/6	3
APOH	ENST00000577982.1	c.461G>A	p.Arg154His	missense_variant	6/6	5

Frequencies

GnomAD3 genomes AF: 0.0732 AC: 11111 AN: 151792 Hom.: 424 Cov.: 31

Gnomad AFR AF: 0.0980

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0471

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.0645

Gnomad SAS AF: 0.0535

Gnomad FIN AF: 0.0900

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0642

Gnomad OTH AF: 0.0704

GnomAD3 exomes AF: 0.0642 AC: 16134 AN: 251354 Hom.: 613 AF XY: 0.0637 AC XY: 8648 AN XY: 135826

Gnomad AFR exome AF: 0.0986

Gnomad AMR exome AF: 0.0298

Gnomad ASJ exome AF: 0.0669

Gnomad EAS exome AF: 0.0615

Gnomad SAS exome AF: 0.0511

Gnomad FIN exome AF: 0.0970

Gnomad NFE exome AF: 0.0671

Gnomad OTH exome AF: 0.0671

GnomAD4 exome AF: 0.0656 AC: 95823 AN: 1460968 Hom.: 3308 Cov.: 32 AF XY: 0.0656 AC XY: 47696 AN XY: 726832

Gnomad4 AFR exome AF: 0.0958

Gnomad4 AMR exome AF: 0.0309

Gnomad4 ASJ exome AF: 0.0698

Gnomad4 EAS exome AF: 0.0716

Gnomad4 SAS exome AF: 0.0500

Gnomad4 FIN exome AF: 0.0948

Gnomad4 NFE exome AF: 0.0658

Gnomad4 OTH exome AF: 0.0614

GnomAD4 genome AF: 0.0732 AC: 11125 AN: 151910 Hom.: 427 Cov.: 31 AF XY: 0.0727 AC XY: 5396 AN XY: 74208

Gnomad4 AFR AF: 0.0980

Gnomad4 AMR AF: 0.0470

Gnomad4 ASJ AF: 0.0712

Gnomad4 EAS AF: 0.0643

Gnomad4 SAS AF: 0.0535

Gnomad4 FIN AF: 0.0900

Gnomad4 NFE AF: 0.0642

Gnomad4 OTH AF: 0.0701

Alfa AF: 0.0666 Hom.: 782

Bravo AF: 0.0702

TwinsUK AF: 0.0645 AC: 239

ALSPAC AF: 0.0693 AC: 267

ESP6500AA AF: 0.0901 AC: 397

ESP6500EA AF: 0.0651 AC: 560

ExAC AF: 0.0658 AC: 7986

Asia WGS AF: 0.0600 AC: 209 AN: 3478

EpiCase AF: 0.0644

EpiControl AF: 0.0688

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2020

This variant is associated with the following publications: (PMID: 25081279) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	14
Dann	Benign	0.57
DEOGEN2	Benign	0.099	T;.;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.52	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.20	N;.;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.61	N;.;.
REVEL	Benign	0.086
Sift	Benign	0.23	T;.;.
Sift4G	Benign	0.12	T;.;.
Polyphen		0.73	P;.;.
Vest4		0.011
MPC		0.19
ClinPred		0.0060	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.035
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8178847; hg19: chr17-64216815; COSMIC: COSV52771858; COSMIC: COSV52771858;