rs1801692

Positions:

• chr17-66226046-C-T

Variant summary

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

The NM_000042.3(APOH):​c.320G>A​(p.Ser107Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,611,824 control chromosomes in the GnomAD database, including 1,557 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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 0.035 (128 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1429 hom.)
• Consequence: APOH NM_000042.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.568

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=0.0023064613).
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APOH	NM_000042.3	c.320G>A	p.Ser107Asn	missense_variant	3/8	ENST00000205948.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APOH	ENST00000205948.11	c.320G>A	p.Ser107Asn	missense_variant	3/8	1	NM_000042.3	P1
APOH	ENST00000581797.5	c.140G>A	p.Ser47Asn	missense_variant	3/6	3
APOH	ENST00000577982.1	c.320G>A	p.Ser107Asn	missense_variant	4/6	5

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5257 AN: 152072 Hom.: 128 Cov.: 33

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.0260

Gnomad SAS AF: 0.0544

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0451

Gnomad OTH AF: 0.0363

GnomAD3 exomes AF: 0.0389 AC: 9723 AN: 250016 Hom.: 249 AF XY: 0.0413 AC XY: 5575 AN XY: 135070

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.0175

Gnomad ASJ exome AF: 0.0524

Gnomad EAS exome AF: 0.0249

Gnomad SAS exome AF: 0.0557

Gnomad FIN exome AF: 0.0364

Gnomad NFE exome AF: 0.0462

Gnomad OTH exome AF: 0.0403

GnomAD4 exome AF: 0.0430 AC: 62702 AN: 1459634 Hom.: 1429 Cov.: 30 AF XY: 0.0437 AC XY: 31741 AN XY: 726046

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.0181

Gnomad4 ASJ exome AF: 0.0549

Gnomad4 EAS exome AF: 0.0150

Gnomad4 SAS exome AF: 0.0558

Gnomad4 FIN exome AF: 0.0369

Gnomad4 NFE exome AF: 0.0448

Gnomad4 OTH exome AF: 0.0425

GnomAD4 genome AF: 0.0345 AC: 5258 AN: 152190 Hom.: 128 Cov.: 33 AF XY: 0.0343 AC XY: 2555 AN XY: 74398

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.0276

Gnomad4 ASJ AF: 0.0550

Gnomad4 EAS AF: 0.0258

Gnomad4 SAS AF: 0.0550

Gnomad4 FIN AF: 0.0392

Gnomad4 NFE AF: 0.0451

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0423 Hom.: 322

Bravo AF: 0.0323

TwinsUK AF: 0.0453 AC: 168

ALSPAC AF: 0.0444 AC: 171

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.0455 AC: 391

ExAC AF: 0.0405 AC: 4921

Asia WGS AF: 0.0560 AC: 193 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	2.2
DANN	Benign	0.51
DEOGEN2	Benign	0.080	T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.43	T;T;T
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.19	N;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.070	N;.;.
REVEL	Benign	0.054
Sift	Benign	1.0	T;.;.
Sift4G	Benign	0.93	T;.;.
Polyphen		0.0	B;.;.
Vest4		0.039
MPC		0.14
ClinPred		0.000017	T
GERP RS		-2.3
Varity_R		0.27
gMVP		0.34

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: rs1801692; hg19: chr17-64222164; COSMIC: COSV52771946;