Genetic Variant APOH:c.-32C>A (chr17-66229411-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000042.3(APOH):c.-32C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0653 in 1,602,734 control chromosomes in the GnomAD database, including 3,551 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.067 ( 326 hom., cov: 32)

Exomes 𝑓: 0.065 ( 3225 hom. )

Consequence

APOH
NM_000042.3 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.59

Publications

21 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0723 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000042.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOH	NM_000042.3	MANE Select	c.-32C>A		5_prime_UTR	Exon 1 of 8	NP_000033.2	A0A384NKM6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APOH	ENST00000205948.11	TSL:1 MANE Select	c.-32C>A	5_prime_UTR	Exon 1 of 8	ENSP00000205948.6	P02749
APOH	ENST00000879112.1		c.-32C>A	5_prime_UTR	Exon 1 of 8	ENSP00000549171.1
APOH	ENST00000879110.1		c.-32C>A	5_prime_UTR	Exon 1 of 8	ENSP00000549169.1

Frequencies

GnomAD3 genomes

AF:

0.0666

AC:

10127

AN:

152100

Hom.:

323

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0744

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0455

Gnomad ASJ

AF:

0.0715

Gnomad EAS

AF:

0.0645

Gnomad SAS

AF:

0.0535

Gnomad FIN

AF:

0.0896

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0642

Gnomad OTH

AF:

0.0664

GnomAD2 exomes

AF:

0.0626

AC:

15405

AN:

246174

AF XY:

0.0625

show subpopulations

Gnomad AFR exome

AF:

0.0746

Gnomad AMR exome

AF:

0.0285

Gnomad ASJ exome

AF:

0.0661

Gnomad EAS exome

AF:

0.0616

Gnomad FIN exome

AF:

0.0970

Gnomad NFE exome

AF:

0.0671

Gnomad OTH exome

AF:

0.0672

GnomAD4 exome

AF:

0.0652

AC:

94573

AN:

1450516

Hom.:

3225

Cov.:

AF XY:

0.0653

AC XY:

47107

AN XY:

721778

show subpopulations

African (AFR)

AF:

0.0728

AC:

2411

AN:

33120

American (AMR)

AF:

0.0299

AC:

1323

AN:

44298

Ashkenazi Jewish (ASJ)

AF:

0.0696

AC:

1809

AN:

25996

East Asian (EAS)

AF:

0.0717

AC:

2829

AN:

39468

South Asian (SAS)

AF:

0.0499

AC:

4244

AN:

84974

European-Finnish (FIN)

AF:

0.0949

AC:

5048

AN:

53216

Middle Eastern (MID)

AF:

0.0714

AC:

410

AN:

5740

European-Non Finnish (NFE)

AF:

0.0661

AC:

72918

AN:

1103768

Other (OTH)

AF:

0.0597

AC:

3581

AN:

59936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

4227

8454

12681

16908

21135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2702

5404

8106

10808

13510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0666

AC:

10138

AN:

152218

Hom.:

326

Cov.:

AF XY:

0.0666

AC XY:

4957

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0745

AC:

3093

AN:

41542

American (AMR)

AF:

0.0454

AC:

695

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0715

AC:

248

AN:

3470

East Asian (EAS)

AF:

0.0643

AC:

333

AN:

5182

South Asian (SAS)

AF:

0.0535

AC:

258

AN:

4822

European-Finnish (FIN)

AF:

0.0896

AC:

948

AN:

10584

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0642

AC:

4368

AN:

68004

Other (OTH)

AF:

0.0662

AC:

140

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

489

979

1468

1958

2447

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0626

Hom.:

455

Bravo

AF:

0.0628

Asia WGS

AF:

0.0580

AC:

200

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

7.0

(source)

DANN

Benign

0.57

PhyloP100

1.6

PromoterAI

0.019

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over