rs1801689

Variant names:

• chr17-66214462-A-C
• rs1801689
• NM_000042.3:c.973T>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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 the same amino acid substitution has been previously reported as Likely benign in 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
APOH	NM_000042.3	c.973T>G	p.Cys325Gly	missense_variant	Exon 7 of 8	ENST00000205948.11	NP_000033.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOH	ENST00000205948.11	c.973T>G	p.Cys325Gly	missense_variant	Exon 7 of 8	1	NM_000042.3	ENSP00000205948.6
APOH	ENST00000585162.1	c.257-2274T>G		intron_variant	Intron 2 of 2	2		ENSP00000462260.1

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

GnomAD2 exomes AF: 0.0245 AC: 6137 AN: 250782 AF XY: 0.0249

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 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 AC: 200 AN: 33442

Gnomad4 AMR exome AF: 0.0273 AC: 1216 AN: 44600

Gnomad4 ASJ exome AF: 0.0590 AC: 1541 AN: 26124

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39694

Gnomad4 SAS exome AF: 0.0164 AC: 1418 AN: 86216

Gnomad4 FIN exome AF: 0.00872 AC: 466 AN: 53420

Gnomad4 NFE exome AF: 0.0312 AC: 34669 AN: 1111668

Gnomad4 Remaining exome AF: 0.0314 AC: 1893 AN: 60354

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 AC: 0.00627947 AN: 0.00627947

Gnomad4 AMR AF: 0.0341 AC: 0.0341132 AN: 0.0341132

Gnomad4 ASJ AF: 0.0628 AC: 0.062788 AN: 0.062788

Gnomad4 EAS AF: 0.000386 AC: 0.000385654 AN: 0.000385654

Gnomad4 SAS AF: 0.0162 AC: 0.0161558 AN: 0.0161558

Gnomad4 FIN AF: 0.00528 AC: 0.00527903 AN: 0.00527903

Gnomad4 NFE AF: 0.0334 AC: 0.0333559 AN: 0.0333559

Gnomad4 OTH AF: 0.0350 AC: 0.0349716 AN: 0.0349716

Alfa AF: 0.0290 Hom.: 310

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
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
Mutation Taster		=36/64	polymorphism (auto)

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;