17-66220697-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 427 hom., cov: 31)

Exomes 𝑓: 0.066 ( 3308 hom. )

Consequence

APOH
NM_000042.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0800

Publications

32 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]

APOH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
APOH	NM_000042.3 link	c.461G>A	p.Arg154His	missense_variant	Exon 5 of 8	ENST00000205948.11	NP_000033.2	P02749A0A384NKM6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
APOH	ENST00000205948.11 link	c.461G>A	p.Arg154His	missense_variant	Exon 5 of 8	1	NM_000042.3	ENSP00000205948.6	P02749
APOH	ENST00000581797.5 link	c.281G>A	p.Arg94His	missense_variant	Exon 5 of 6	3		ENSP00000463553.1	J3QLI0
APOH	ENST00000577982.1 link	c.461G>A	p.Arg154His	missense_variant	Exon 6 of 6	5		ENSP00000464301.1	J3QRN2
APOH	ENST00000585162.1 link	c.-68G>A		upstream_gene_variant		2		ENSP00000462260.1	J3KS17

Frequencies

GnomAD3 genomes

AF:

0.0732

AC:

11111

AN:

151792

Hom.:

424

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0642

AC:

16134

AN:

251354

AF XY:

0.0637

show subpopulations

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 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.:

AF XY:

0.0656

AC XY:

47696

AN XY:

726832

show subpopulations

African (AFR)

AF:

0.0958

AC:

3199

AN:

33404

American (AMR)

AF:

0.0309

AC:

1383

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0698

AC:

1823

AN:

26120

East Asian (EAS)

AF:

0.0716

AC:

2841

AN:

39690

South Asian (SAS)

AF:

0.0500

AC:

4309

AN:

86226

European-Finnish (FIN)

AF:

0.0948

AC:

5065

AN:

53414

Middle Eastern (MID)

AF:

0.0718

AC:

414

AN:

5766

European-Non Finnish (NFE)

AF:

0.0658

AC:

73081

AN:

1111250

Other (OTH)

AF:

0.0614

AC:

3708

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

4360

8720

13081

17441

21801

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0732

AC:

11125

AN:

151910

Hom.:

427

Cov.:

AF XY:

0.0727

AC XY:

5396

AN XY:

74208

show subpopulations

African (AFR)

AF:

0.0980

AC:

4061

AN:

41418

American (AMR)

AF:

0.0470

AC:

717

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.0712

AC:

247

AN:

3468

East Asian (EAS)

AF:

0.0643

AC:

332

AN:

5164

South Asian (SAS)

AF:

0.0535

AC:

258

AN:

4822

European-Finnish (FIN)

AF:

0.0900

AC:

943

AN:

10478

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0642

AC:

4365

AN:

67996

Other (OTH)

AF:

0.0701

AC:

148

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

521

1042

1564

2085

2606

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0675

Hom.:

1465

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:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 28, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.099

T;.;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.52

T;T;T

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.20

N;.;.

PhyloP100

0.080

PrimateAI

Benign

0.23

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

GERP RS

1.6

PromoterAI

-0.035

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.39

Mutation Taster

=85/15

polymorphism (auto)

(source)

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

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17-66220697-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over