rs1801689

Positions:

• chr17-66214462-A-C
• chr17-66214462-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000042.3(APOH):​c.973T>G​(p.Cys325Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0281 in 1,613,586 control chromosomes in the GnomAD database, including 770 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.023 (57 hom., cov: 32)
  • Exomes 𝑓: 0.029 (713 hom.)
• Consequence: APOH NM_000042.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.76

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010155737).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOH	NM_000042.3	c.973T>G	p.Cys325Gly	missense_variant	7/8	ENST00000205948.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOH	ENST00000205948.11	c.973T>G	p.Cys325Gly	missense_variant	7/8	1	NM_000042.3	P1
APOH	ENST00000585162.1	c.258-2274T>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3503 AN: 152188 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0342

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.00528

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0353

GnomAD3 exomes AF: 0.0245 AC: 6137 AN: 250782 Hom.: 120 AF XY: 0.0249 AC XY: 3369 AN XY: 135542

Gnomad AFR exome AF: 0.00585

Gnomad AMR exome AF: 0.0252

Gnomad ASJ exome AF: 0.0583

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.00818

Gnomad NFE exome AF: 0.0328

Gnomad OTH exome AF: 0.0344

GnomAD4 exome AF: 0.0286 AC: 41833 AN: 1461280 Hom.: 713 Cov.: 31 AF XY: 0.0287 AC XY: 20879 AN XY: 726976

Gnomad4 AFR exome AF: 0.00598

Gnomad4 AMR exome AF: 0.0273

Gnomad4 ASJ exome AF: 0.0590

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.00872

Gnomad4 NFE exome AF: 0.0312

Gnomad4 OTH exome AF: 0.0314

GnomAD4 genome AF: 0.0230 AC: 3499 AN: 152306 Hom.: 57 Cov.: 32 AF XY: 0.0220 AC XY: 1636 AN XY: 74474

Gnomad4 AFR AF: 0.00628

Gnomad4 AMR AF: 0.0341

Gnomad4 ASJ AF: 0.0628

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.00528

Gnomad4 NFE AF: 0.0334

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0300 Hom.: 146

Bravo AF: 0.0239

TwinsUK AF: 0.0332 AC: 123

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.0364 AC: 313

ExAC AF: 0.0240 AC: 2919

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.010	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.33
MPC		0.75
ClinPred		0.042	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs1801689; hg19: chr17-64210580; COSMIC: COSV52772605; COSMIC: COSV52772605;